Matching chelators to radiometals for radiopharmaceuticals

Abstract

Radiometals comprise many useful radioactive isotopes of various metallic elements. When properly harnessed, these have valuable emission properties that can be used for diagnostic imaging techniques, such as single photon emission computed tomography (SPECT, e.g.⁶⁷Ga, ^99mTc, ¹¹¹In, ¹⁷⁷Lu) and positron emission tomography (PET, e.g.⁶⁸Ga, ⁶⁴Cu, ⁴⁴Sc, ⁸⁶Y, ⁸⁹Zr), as well as therapeutic applications (e.g.⁴⁷Sc, ^114mIn, ¹⁷⁷Lu, ⁹⁰Y, ^212/213Bi, ²¹²Pb, ²²⁵Ac, ^186/188Re). A fundamental critical component of a radiometal-based radiopharmaceutical is the chelator, the ligand system that binds the radiometal ion in a tight stable coordination complex so that it can be properly directed to a desirable molecular target in vivo. This article is a guide for selecting the optimal match between chelator and radiometal for use in these systems. The article briefly introduces a selection of relevant and high impact radiometals, and their potential utility to the fields of radiochemistry, nuclear medicine, and molecular imaging. A description of radiometal-based radiopharmaceuticals is provided, and several key design considerations are discussed. The experimental methods by which chelators are assessed for their suitability with a variety of radiometal ions is explained, and a large selection of the most common and most promising chelators are evaluated and discussed for their potential use with a variety of radiometals. Comprehensive tables have been assembled to provide a convenient and accessible overview of the field of radiometal chelating agents.

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Eric W. Price and Chris Orvig

Eric Price received his undergraduate education at the University of Victoria in Victoria, British Columbia, Canada, where he completed his honours BSc (2009) in Chemistry as a part of the CO-OP program, performing research both in industry and academia, including work at TRIUMF and an NSERC USRA research term with Dr Matthew Moffitt. In 2009 he began his PhD studies as an NSERC scholar in a joint project between Dr Chris Orvig at the University of British Columbia and Dr Michael J. Adam at TRIUMF, partially in collaboration with Nordion, researching new radiometal-based radiopharmaceuticals of ^67/68Ga, ^64Cu, ^111In, ^177Lu, ^89Zr, and ^225Ac. He initiated, and has been pivotal in, an international research collaboration with Dr Jason S. Lewis and Dr Brian M. Zeglis, traveling to Memorial Sloan-Kettering Cancer Center in New York, USA, and has also collaborated with the BC Cancer Agency in Vancouver, as part of his PhD work. In 2013 he won the Berson–Yalow award from the Society of Nuclear Medicine and Molecular Imaging.

Chris Orvig earned his Hons. BSc from McGill and his PhD as an NSERC of Canada scholar at MIT with Alan Davison, FRS. After postdoctoral fellowships with Kenneth N. Raymond at the University of California, Berkeley, and the late Colin J. L. Lock at McMaster University, he joined the University of British Columbia in 1984, where he is now Professor of Chemistry and Pharmaceutical Sciences. Orvig, a Fellow of the Royal Society of Canada, has received various teaching, research and service awards, and published more than 200 research papers. He is a co-inventor on many issued patents, and a certified ski instructor.

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1. Introduction

Radiometals are radioactive isotopes that can be harnessed for applications in medical diagnosis, as well as for cancer therapy. In order to apply these isotopes to specific biological applications, the “free” radiometal ions must be sequestered from aqueous solution using chelators (ligands) to obviate transchelation and hydrolysis. Chelators used for this application are typically covalently linked to a biologically active targeting molecule, making an active radiopharmaceutical agent. The chelator is used to tightly bind a radiometal ion so that when injected into a patient, the targeting molecule can deliver the isotope without any radiometal loss from the radiopharmaceutical, effectively supplying a site-specific radioactive source in vivo for imaging or therapy. A rapidly expanding number of radiometals are routinely produced, with a broad variety of half-lives, emission types, energies, and branching ratios (Table 1).^1–4 The availability of a wide range of radiometal ions makes it possible to carefully pick the specific nuclear properties that are needed for a vast number of different applications. Some examples of radiometals that can be used for positron emission tomography (PET) imaging are ⁶⁸Ga, ⁶⁴Cu, ⁸⁶Y, ⁸⁹Zr, and ⁴⁴Sc, with PET imaging providing sensitive, quantitative, and non-invasive images of a variety of molecular processes and targets. Single photon emission computed tomography (SPECT) is an older and more ubiquitous imaging modality than PET, and, since its inception in the 1960s, ^99mTc has been the workhorse isotope of SPECT. More recently, the radiometals ⁶⁷Ga, ¹¹¹In, and ¹⁷⁷Lu have been increasingly used for SPECT imaging in chelator-based radiopharmaceuticals. For therapy applications, particle emitters such as ¹¹¹In (Auger electron emitter), ⁹⁰Y and ¹⁷⁷Lu (β⁻), and ²²⁵Ac, ²¹²Pb, and ²¹³Bi (α), are being heavily investigated, typically in conjunction with antibody vectors (immunoconjugates) or peptides. Each radiometal ion has unique aqueous coordination chemistry properties; these must be properly attended to if these isotopes are to be safely harnessed for medical applications and use in vivo.

Table 1 Properties of some popular radiometal isotopes, EC = electron capture; some low abundance emissions have been omitted for brevity^1–4,15,16

Isotope	t 1/2 (h)	Decay mode	E (keV)	Production method
^60Cu	0.4	β^+ (93%)	β^+, 3920, 3000, 2000	Cyclotron, ^60Ni(p,n)^60Cu
		EC (7%)
^61Cu	3.3	β^+ (62%)	β^+, 1220, 1150, 940, 560	Cyclotron, ^61Ni(p,n)^61Cu
		EC (38%)
^62Cu	0.16	β^+ (98%)	β^+, 2910	^62Zn/^62Cu generator
		EC (2%)
^64Cu	12.7	β^+ (19%)	β^+, 656	Cyclotron, ^64Ni(p,n)^64Cu
		EC (41%)
		β^− (40%)
^66Ga	9.5	β^+ (56%)	β^+, 4150, 935	Cyclotron, ^63Cu(α,nγ)^66Ga
		EC (44%)
^67Ga	78.2	EC (100%)	γ, 93, 184, 300	Cyclotron, ^68Zn(p,2n)^67Ga
^68Ga	1.1	β^+ (90%)	β^+, 1880	^68Ge/^68Ga generator
		EC (10%)
^44Sc	3.9	β^+ (94%)	γ, 1157	^44Ti/^44Sc generator
		EC (6%)	β^+, 1474
^47Sc	80.2	β^− (100%)	γ, 159	^47Ti(n,p)^47Sc
			β^−, 441, 600
^111In	67.2	EC (100%)	γ, 245, 172	Cyclotron, ^111Cd(p,n)^111m,gIn
^114mIn	49.5 d	EC (100%)	γ, 190	Cyclotron, ^114Cd(p,n)^114mIn or ^116Cd(p,3n)^114mIn
^114In (daughter)	73 s	β^− (100%)	β^−, 1989
^177Lu	159.4	β^− (100%)	γ, 112, 208	^176Lu(n,γ)^177Lu
			β^−, 177, 385, 498
^86Y	14.7	β^+ (33%)	β^+, 1221	Cyclotron, ^86Sr(p,n)^86Y
		EC (66%)
^90Y	64.1	β^− (100%)	β^−, 2280	^90Zr(n,p)^90Y
^89Zr	78.5	β^+ (23%)	β^+, 897	Cyclotron, ^89Y(p,n)^89Zr
		EC (77%)
^212Bi	1.1	α (36%)	α, 6050	^228Pb/^212Pb generator
		β^− (64%)	β^−, 6089
^213Bi	0.76	α (2.2%)	α, 5549	^228Th/^212Pb generator
		β^− (97.8%)	β^−, 5869
^212Pb (daughter is ^212Bi)	10.6	β^− (100%)	α, 570	^224Ra/^212Pb generator
^225Ac	240	α (100%)	α, 5600–5830 (6)	^226Ra(p,2n)^225Ac
				n-Capture of ^232Th → ^233U → ^225Ac

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The major difference between radioactive (“hot”) and non-radioactive (“cold”) metal ion chemistry is that radiochemistry is typically performed under extremely dilute conditions, with radiometal ions typically being utilized at nM to pM concentrations.⁵ It is also important to note that several of the elements being discussed have multiple radioactive isotopes that are useful for diagnostic or therapeutic purposes (e.g.^86/90Y, ^67/68Ga, ^44/47Sc, ^60/61/62/64Cu), and all isotopes of a given element have identical chemistry.^6–11 This means that a single radiopharmaceutical agent can be radiolabeled with different isotopes of the same element (e.g.^86/90Y), and provide the same charge and physical properties, and therefore the same biological behavior and distribution in vivo.^6–11 This class of radiopharmaceutical that utilizes two isotopes of the same element, such as ⁸⁶Y for PET imaging and ⁹⁰Y for therapy, has been referred to as a theranostic agent.^12,13 An interesting note about ⁹⁰Y is that as a β⁻ emitter it is possible to perform biodistribution, imaging, and dosimetry studies with its bremsstrahlung X-rays, but because the spatial resolution and image quality obtained is very poor an imaging surrogate is typically used (e.g.¹¹¹In or ⁸⁶Y).¹⁴ Alternatively, ⁹⁰Y is unique and in some circumstances can be used directly for PET imaging because it emits a very low abundance of positrons (0.003%), which can be used to collect imaging data superior to that obtained by ⁹⁰Y bremsstrahlung imaging.¹⁴

2. Radiometal-based radiopharmaceutical design

Ligands that are typically used to construct radiometal-based radiopharmaceuticals (not always with ^99mTc) are bifunctional chelators (BFCs), which are simply chelators with reactive functional groups that can be covalently coupled (conjugated) to targeting vectors (e.g. peptides, nucleotides, antibodies, nanoparticles). Common bioconjugation techniques utilize functional groups such as carboxylic acids or activated esters (e.g. N-hydroxysuccinimide NHS-ester, tetrafluorophenyl TFP-ester) for amide couplings, isothiocyanates for thiourea couplings, and maleimides for thiol couplings (Fig. 1).^17,18 Click chemistry is gaining popularity in bioconjugate chemistry, with both the traditional copper(I) catalyzed azide–alkyne Huisgen 1,3-dipolar cycloaddition “click” reaction (forming a 1,2,3-triazole-ring linkage), or newer copper-free reactions like strain-promoted azide–alkyne cycloadditions (e.g. dibenzocyclooctyne/azide reaction) and Diels–Alder click reactions (e.g. transcyclooctene/1,2,4,5-tetrazine) (Fig. 1).¹⁹ It is interesting to note that the transcyclooctene/1,2,4,5-tetrazine copper-free click coupling displays remarkably fast reaction kinetics, allowing for novel applications like in vivo pre-targeting, where the click reaction can occur in vivo at very dilute concentrations.^20–24 The modular design of BFC systems allows for a theoretically limitless number of different vectors to be conjugated, providing molecular targeting to a constantly increasing number of biological targets.

Fig. 1 Examples of bioconjugation reactions: (A) standard peptide coupling reaction between a carboxylic acid and a primary amine with a coupling reagent; (B and C) peptide coupling reactions between activated esters of tetrafluorophenyl (TFP) or N-hydroxysuccinimide (NHS) and a primary amine; (D) thiourea bond formation between an isothiocyanate and a primary amine; (E) thioether bond formation between a maleimide and thiol; (F) standard Cu(I) catalyzed Huisgen 1,3-dipolar cycloaddition (“click” reaction) between an azide and an alkyne; and (G) strain-promoted Diels–Alder “click” reaction between a tetrazine and transcyclooctene.

The structure and physical properties of the radiometal–chelate complex have a large impact on the overall pharmacokinetic properties of a radiopharmaceutical, with many radiometal complexes being very hydrophilic and subsequently leading to rapid renal excretion when attached to small vectors like peptides and nucleotides (less prominent with large ∼150 kDa antibodies).^6–11,179 It has been observed in peptide-conjugates that keeping the radiometal ion and peptide constant, and changing only the chelator can have drastic effects on biodistributions.²⁵ Radiometal-based radiopharmaceuticals contain many synthetically exchangeable components, which can be separated into different modules: the radiometal, which changes the radioactive emission properties and half-life (γ for SPECT, β⁺ for PET, and β⁻ or α particles, or Auger electrons, for therapy); the chelator, which must be carefully matched with the radiometal for optimal stability; the BFC–vector conjugation method, for different types of bioconjugation reactions and linkages; and the vector/targeting moiety, which allows for the selection of any known molecular target for site-specific delivery of the radioactive “payload” (Fig. 2).

Fig. 2 Illustration of an archetypal radiometal-based radiopharmaceutical agent containing a bifunctional chelator (BFC) conjugated to a targeting vector (e.g. antibody, peptide, nanoparticle) using a variety of conjugation methods (e.g. isothiocyanate–amine coupling, peptide coupling, maleimide–thiol coupling, activated ester amide coupling, click-coupling) and then radiolabeled with a radiometal ion (e.g.¹¹¹In³⁺/¹⁷⁷Lu³⁺/^86/90Y³⁺).

Each radiometal ion has different chemical demands, including ligand donor atom preferences (e.g. N, O, S, hard/soft), coordination number, and coordination geometry; however, there are many key design considerations that can be applied universally.²⁶ Ligand synthesis should be relatively simple and avoid stereoisomers and non-enantio/diastereospecific reactions, modularity should be incorporated in BFC synthesis as much as possible to allow for incorporation of different bioconjugation handles, and modular synthesis also should allow for tuning of denticity and physical properties by changing the polarity and charge of the chelate (the degree of polarity can be assessed by octanol–water partition coefficients (log P)), so that biodistribution properties can be adjusted.

The intention of this article is to act as a guide for researchers to find the optimal match of chelator with radiometal for radiopharmaceutical applications. The methods by which chelators are evaluated with different radiometals will be discussed, and the current “gold standard” chelators for each relevant radiometal ion will be identified. A large number of review articles with broader scopes have been written that discuss the application of radiometals in radiopharmaceuticals, covering topics ranging from chelators, coordination chemistry, synthetic methodologies, radiometal production, radiochemistry, bioconjugation strategies, automation, molecular targeting groups (vectors), imaging modalities, and therapeutics.^{3,13,15,17,18,26–51} Technetium chemistry is not covered here, because the chemistry of technetium, and the types of ligands used with it, differ drastically from those for the radiometals discussed here.^26,35,52

2.1 Macrocyclic versus acyclic chelators

When designing new chelators, a historical glance at previous work reveals that macrocycles are generally more kinetically inert than acyclic chelators, even if their thermodynamic stabilities have been determined to be very similar.^53–57 Macrocyclic chelators require minimal physical manipulation during metal ion coordination, as they possess inherently constrained geometries and partially pre-organized metal ion binding sites, thereby decreasing the entropic loss experienced upon metal ion coordination.⁵⁸ To contrast this, acyclic chelators must undergo a more drastic change in physical orientation and geometry in solution in order to arrange donor atoms to coordinate with a metal ion, and subsequently they suffer a more significant decrease in entropy than do macrocycles (thermodynamically unfavorable). The thermodynamic driving force towards complex formation is therefore greater for macrocycles in general, a phenomenon referred to as the macrocycle effect.⁵⁸ A crucial property where most acyclic chelators excel and most macrocycles suffer is in the coordination kinetics and radiolabeling efficiency. The ability to quantitatively radiolabel/coordinate a radiometal in less than 15 minutes at room temperature is a common property of acyclic chelators, whereas macrocycles often require heating to 60–95 °C for extended times (30–90 minutes).^59–61 Fast room temperature radiolabeling becomes a crucial property when working with BFC-conjugates of heat sensitive molecules such as antibodies and their derivatives, or when working with short half-life isotopes such as ⁶⁸Ga, ^212/213Bi, ⁴⁴Sc, and ⁶²Cu.

2.2 Matching chelators with radiometals – how are chelators evaluated?

When a new chelator is synthesized for the purpose of radiometal ion sequestration, or an old chelator is repurposed for use with a new radiometal ion, initial screening experiments are usually done by simple radiolabeling to determine a number of factors: whether the chelator can bind the radiometal ion and effectively radiolabel in high yields (quantitative is best), what temperature is required (ambient temperature is best), and what reaction time is required (faster is better). Short half-life isotopes like ⁶⁸Ga are ideally matched with chelators that can radiolabel rapidly (fast radiolabeling kinetics). Longer half-life isotopes such as ¹¹¹In and ¹⁷⁷Lu allow for extended reaction times, but even if the half-life allows for long reaction times, completing the radiolabeling portion of radiopharmaceutical preparation is most convenient if finished in less than 10 or 15 minutes. As previously mentioned, room temperature radiolabeling is crucial for sensitive antibody vectors, which are degraded at elevated temperatures. DOTA inconveniently requires elevated temperatures for radiolabeling with essentially all radiometals (e.g.⁴⁴Sc, ¹¹¹In, ¹⁷⁷Lu, ^86/90Y, ²²⁵Ac) but its abundant application in radiochemistry for decades, its exceptional in vivo stability, and the commercial availability of many different bifunctional DOTA derivatives and vector conjugates means that it is likely the most commonly used chelator to this day. Moving forward to the design and testing of new chelators, fast room temperature radiolabeling kinetics should be a priority; however, fast kinetics of radiometal incorporation (on-rate) and consequently low energetic barriers to radiometal–chelate complexation can also mean fast radiometal decorporation (off-rates) and low energetic barriers to radiometal release (Fig. 3). An arduous balancing act is required to obtain the best set of chelate properties for each application and radiometal ion, requiring the study and availability of a broad selection of different chelators with a variety of properties from which to choose.

Fig. 3 Cartoon depiction of metal ion coordination kinetics, enhanced off-rate kinetics in vivo (extremely dilute conditions), and possible routes of radiometal ion loss in vivo (solid-state structures of ferritin H-chain homopolymer PDB file 1FHA, ceruloplasmin PDB file 2J5W, and apo-transferrin PDB file 2HAV shown).

When a chelator is identified through early screening to possess radiolabeling properties that are suitable for use with a particular radiometal ion, it must then be experimentally determined to be highly stable and inert. Further experiments are performed with the specific radiometal–chelate complex under conditions relevant to in vivo translation to judge its potential as the core component of a radiometal-based radiopharmaceutical. The result of radiometal loss from a radiopharmaceutical in vivo is the non-targeted distribution of the “free” radiometal ion in the body, and its exact fate and distribution in the body depends on the properties and biological behavior of the specific radiometal ion in question (Fig. 3). For example, ⁸⁹Zr and ⁶⁸Ga are known to accumulate in the bone when released from a BFC, where ⁶⁴Cu is known to accumulate in the liver. The fate of these radiometal ions can be tracked using PET/SPECT imaging in the living animal, and/or biodistribution experiments where animals are euthanized at predetermined time points, their organs harvested, and the distribution of radioactivity measured and calculated for the percentage of injected dose of radioactivity per gram of tissue (%ID/g). Each metal ion has its own unique properties that must be considered when constructing a radiometal-based imaging/therapeutic agent, such as its aqueous hydrolysis chemistry, redox chemistry, and affinity for native biological chelators.

2.3 Thermodynamic stability

When evaluating and selecting a chelator to match with a specific radiometal ion for use in a radiopharmaceutical, kinetic inertness in vivo is ultimately the most crucial consideration, even beyond that of the absolute thermodynamic stability of the metal–chelate complex. Thermodynamic stability/formation constants (K_ML = [ML]/[M][L]) are usually experimentally determined by potentiometric and/or spectrophotometric titrations, but evaluating kinetic inertness under conditions relevant to in vivo applications can be much more problematic. Thermodynamic stability constants can be a useful metric for preliminary comparisons of various chelators with a particular metal ion, but they do not predict in vivo stability with any level of competence.^62,63 A thermodynamic parameter that provides more biologically relevant information than K_ML values is the pM value (−log[M]_Free).^64–67 The pM value is the negative log of the concentration of free metal ion uncomplexed by a given chelator under specific conditions. The pM value is a condition-dependent value that is calculated from the standard thermodynamic stability constant (log K_ML), accounting for variables and conditions such as ligand basicity, metal ion hydrolysis, (physiological) pH, and ligand : metal ratio.

Stability constants and pM values provide a number for the direction and magnitude of the equilibrium in a metal–chelate coordination reaction under specific conditions, but give no kinetic information (e.g. off-rates for dissociation).^68,69 This is a very important factor because the rate of dissociation in vivo is what governs the kinetic inertness of a radiometal complex, regardless of thermodynamic stability, and these off-rates are greatly influenced by the high dilution encountered in vivo when a tiny quantity of radiopharmaceutical (micro- or nano-grams) is diluted into the blood pool (Fig. 3). Even more complicating is the abundant presence in the body of many strong native biological chelators and competing ions that can transchelate radiometals from BFC-conjugates. These are often present in higher concentrations than is the radiopharmaceutical, and include transport proteins such as transferrin, ceruloplasmin, and metallothionein, storage proteins like ferritin, and metal containing enzymes such as superoxide dismutase (Fig. 3). This wide range of complicating factors means that a single in vitro assay is typically not accurate in predicting in vivo stability.

2.4 Kinetics – acid dissociation and competitive radiolabeling

Acid dissociation experiments can be used to measure and assess the relative kinetic inertness of a metal complex to acidic conditions. Most complexes are found to de-ligate fairly quickly below pH 2.0,⁷⁰ and experiments evaluating the rate of dissociation at a constant pH (e.g. 2.0) have been performed to compare and evaluate chelators with a particular metal/radiometal ion.^55,70,71 In these acid dissociation experiments, decomplexation can be observed over time with techniques such as high-performance liquid chromatography (HPLC), thin-layer chromatography (TLC), and nuclear magnetic resonance (NMR) for diamagnetic metal complexes. With the exception of copper chelates,^68,72 acid dissociation experiments are not commonly performed as they do not provide an accurate prediction of in vivo kinetic inertness, because low pH is not encountered in the blood or most organs (except the stomach) and radiometal dissociation typically occurs via transchelation to serum proteins and enzymes, and is not acid-mediated.^69,73–77

Competitive radiolabeling experiments can be performed by adding to a radiolabeling mixture an excess of non-radioactive ions, such as Na⁺, K⁺, Ca²⁺, Mg²⁺, Cu²⁺, Zn²⁺, or Fe³⁺, followed by addition of a chelator to evaluate the impact of these competing ions on radiolabeling yields.^55,78–81 These experiments can reveal the radiolabeling selectivity of a chelator for a specific radiometal ion in the presence of other biologically relevant competing ions. Alternatively, if the radiometal complex is preformed under standard metal-free radiolabeling conditions, and is then added to a mixture containing these competing ions, stability to transchelation can be assessed. Because chelate-based radiopharmaceuticals are typically radiolabeled in strictly metal-free conditions (deionized ultrapure water, often passed through a metal-scavenging chelex resin), these experiments may not appear completely relevant for predicting in vivo stability and utility. Depending on the method of radiometal production and purification, the specific activity of radiometal ions can vary greatly, as can the concentrations of impurity metals ions.⁵ Radiometals are used in very small quantities and under extremely dilute conditions; therefore, any impurity metal ions present (even if only a few nanomoles) may actually be in excess of the radiometal ion concentration, and competitive binding could be problematic.^5,82 The presence and quantity of metal ion impurities in radiometal mixtures depends on the source of the radiometal ion, method of production, and purification.^5,82

2.5 In vitro and in vivo stability

Experiments that are more pertinent to in vivo translation are metal-exchange competitions with biologically relevant mixtures, including blood serum, apo-transferrin, superoxide dismutase, and hydroxyapatite (bone).^18,83–88 By incubating radiometallated chelators with these different competition mixtures, the quantity of radiometal that is transchelated from chelator to serum proteins/enzymes can be evaluated over time using size exclusion HPLC, iTLC, or disposable PD10 size exclusion columns.^18,83–88 These experiments provide a directly relevant measure of stability and kinetic inertness by competition with the most likely transchelation culprits in vivo; additionally, in these in vitro assays the concentrations of these biological reagents can often be elevated above normal physiological levels to provide a more stringent challenge.

Ultimately the most relevant and practical test of radiopharmaceutical stability is in vivo. Biodistribution studies in healthy mice can be performed on “naked” radiometal–chelate complexes (no conjugated vectors) to assess clearance and uptake profiles and ensure no abnormal organ distribution or critical instability occurs. If a radiometal–chelate complex is very stable in vivo, the complex is typically cleared quickly from the animal through the kidneys/bladder/urine or digestive system/liver/feces depending on polarity and metabolism.⁸⁹ Unstable complexes often demonstrate persistent uptake in organs and tissues where the non-bound radiometal is known to associate (e.g. Zr⁴⁺ and lanthanides in the bone, Cu²⁺ in the liver).⁸⁹ The major drawback to this type of experiment with “naked” chelate complexes is that highly polar and charged radiometal–chelate complexes are typically cleared very quickly from the body, and therefore do not persist in vivo for long enough to encounter any significant challenge to their structural integrity.^84,85 Conversely, highly lipophilic complexes tend to accumulate in the liver and digestive tract, regardless of stability.^84,85

To evaluate properly the stability and kinetic inertness of a chelate in vivo, a suitable vector must be attached (e.g. peptide, antibody, nanoparticle) so that the radiometal–chelate complex is made to persist in blood circulation for a substantial period of time, and can be monitored over several hours or days (depending on isotope half-life and the subsequent imaging/therapy window).⁹⁰ An additional concern with in vivo experiments is the significant normal variance between animals that introduces error; for example, 10 mice of the same sex and breed, procured from the same supplier, will often show significant differences in biodistribution of the same radiopharmaceutical. Additionally, the specific experimental techniques and methods (e.g. radiopharmaceutical preparation, injection, animal dissection, organ counting) used for these biodistribution experiments can cause large variability between data sets. Variables such as specific activity of the source radiometal, specific activity of the radiolabeled agent, radiolabeling temperature, purity of the final radiopharmaceutical preparation, injected mass of radiopharmaceutical, and injected volume can make large differences in biodistribution profiles. The same radiopharmaceutical used at different institutions may offer drastically different tumor uptake and organ distribution values, if the above variables are not tightly controlled, and even then differences between animals and between experimental techniques can introduce large variances. For these reasons it is crucial to include internal control experiments for every study; for example, evaluation of a new chelator in vivo should be done in parallel with an existing and established “gold standard” chelator so that a direct comparison can be made because comparison to previously performed studies (even in the exact same animal model and/or cell line) is often not reliable due to the above mentioned complications.^79,83,85,91

3. A selection of chelators and their most suitable radiometal companions

A survey of radiometal chelators has been undertaken, with the most relevant and promising examples being discussed. The most suitable chelate–radiometal matches have been identified, and detailed tables included, with the aim of providing a quick reference for those looking to find the optimal match between chelator and radiometal. A color-coding scheme has been used, and justification for the assignment of good (green), fair (orange), and poor (red) matches between chelators and radiometals can be found in the text and the provided references. The color code indicates the authors' opinions on the general suitability of a chelator for use with a specific radiometal, accounting for factors such as radiolabeling conditions and in vitro/in vivo stability. An assignment of green may suggest that either a chelator is currently the “gold standard” for use with a given radiometal, or that early work with a new chelator looks very promising and in vivo studies have shown that it works comparably to the current “gold standards”. Assignment of orange to a chelator–radiometal pair may be made if the combination has been used in vivo successfully, but perhaps in recent years has been surpassed by a new and superior chelator and is no longer the best choice. Also, an assignment of orange could mean that a new chelator–radiometal ion pair looks very promising, but perhaps a bifunctional derivative has yet to be synthesized, or only preliminary in vivo work has been done and more study is required (e.g. no study of bioconjugates, or no direct comparisons to existing “gold standards” for internal reference). An assignment of red indicates that the highlighted chelator–radiometal ion pair is an unsuitable match, and generally should not be used due to severe instability or radiolabeling problems. These color “ratings” were made using the referenced studies and reflect the current trends in radiochemistry and nuclear medicine, with the goal of acting as a quick guide for those seeking to find an optimal chelate–radiometal ion pairing.

3.1 DOTA

DOTA is one of the primary workhorse chelators for radiometal chemistry, and is one of the current “gold standards” for a number of isotopes, including ¹¹¹In, ¹⁷⁷Lu, ^86/90Y, ²²⁵Ac, and ^44/47Sc. DOTA has been extensively used with ^67/68Ga, but is widely accepted to be less stable than its more petite macrocyclic counterpart NOTA (Table 2). ⁶⁸Ga-DOTATOC has been shown to exhibit superior in vivo properties to ¹¹¹In-DOTATOC (Octreoscan) despite non-optimal stability.⁹² Even though a chelator may be more stable and inert with a given radiometal (e.g. NOTA vs. DOTA for ⁶⁸Ga), it may not be the optimal choice for a certain application (e.g. a specific peptide vector). For example, NOTA is widely accepted to form a more stable complex with ⁶⁸Ga than does DOTA, but due to differences in charge and physical properties (e.g. neutral vs. charged complex), DOTA may provide superior in vivo properties with certain vectors.^25,79 This example highlights the complex set of variables one must consider when constructing radiometal-based radiopharmaceuticals.

Table 2 DOTA and bifunctional derivatives, highlighting relevant radiometal ions, radiolabeling conditions, thermodynamic stability constants (log K_ML), coordination geometry, and color-coded ranking

Chelator and common bifunctional derivatives	Radiometal ion		Radiolabeling conditions	log KML	Proposed geometry	Ref.
a Green “✓” = good/best match, orange “∼” = suitable match, or requires more evaluation but shows potential, red “✗” = poor/unstable match.
DOTA, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, maximum CN = 8, donor set N4O4	^64Cu^2+		25–90 °C, 30–60 min, pH 5.5–6.5	22.2, 22.7	Distorted octahedron	84, 87, 90, 104–110
	^67/68Ga^3+		37–90 °C, 10–30 min, pH 4.0–5.5	21.3 (pM 15.2, 18.5)	Distorted octahedron	64, 92, 110–118
	^44/47Sc^3+		95 °C, 20–30 min, pH 4.0	27.0 (pM 26.5)	Square antiprism	96–98
	^111In^3+		37–100 °C, 15–60 min, pH 4.0–6.0	23.9 (pM 17.8–18.8)	Square antiprism?	64, 85, 93, 114, 117, 119–124, 179
	^177Lu^3+		25–100 °C, 15–90 min, pH 4.0–6.0	23.5, 21.6 (pM 17.1)	Square antiprism	124–130
	^86/90Y^3+		25–100 °C, 15–90 min, pH 4.0–6.0	24.3–24.9	Square antiprism	55, 70, 93, 124, 127, 130–132
	^213Bi^3+		95–100 °C,^133 5 min, pH 6.0–8.7	—	Square antiprism	134, 135
	^212Pb^2+		25–75 °C, 30–60 min, pH 4.0–5.5	—	Square antiprism	127, 136–138
	^225Ac^3+		37–60 °C, 30–120 min, pH 6.0	—	Square antiprism?	100, 101
DOTA-NHS-ester^139	p-SCN-Bn-DOTA (C-DOTA)^95,140,141		DOTAGA, R = amide, NHS ester^142		DOTAGA-anhydride^143

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When designing new BFCs or modifying existing chelators to make BFC derivatives, care should be taken not to disrupt the original coordination sphere of the chelator. Some common bifunctional DOTA derivatives utilize one of the carboxylic acid arms for the site of vector conjugation, effectively blocking one of the coordinating carboxylate arms (amide carbonyl groups may still coordinate, albeit weakly) (Table 2).⁵⁹ DOTAGA, DOTASA, and various isothiocyanate derivatives of DOTA have been synthesized and solve this problem by conjugating to vectors through the carbon backbone and side-arm functionalization (Table 2).^59,93–95 These bifunctional DOTA derivatives retain their maximum potential denticity (octadentate) as well as the same thermodynamic stability and kinetic inertness as unadulterated DOTA.^59,93,94

Despite its slow radiolabeling kinetics and required heating, DOTA is currently the “gold standard” chelator for use with ¹¹¹In, ¹⁷⁷Lu, and ^86/90Y (Table 2). The coordination chemistry and properties of Y³⁺ and Lu³⁺ are very similar; they both preferentially form 8–9 coordinate complexes in square antiprismatic or monocapped square antiprismatic geometries, and are hard metal ions with a preference for hard ligand donors such as carboxylate-oxygens and amine-nitrogens. In³⁺ has similar properties to Y³⁺ and Lu³⁺, but being smaller forms 7–8 coordinate complexes, typically with square antiprismatic geometry. According to acid dissociation experiments performed at pH 2.0 with the ⁹⁰Y complexes of DOTA, DTPA (vide infra), and CHX-A′′-DTPA, DOTA is the most kinetically inert to acid dissociation by a significant margin, with CHX-A′′-DTPA showing moderate stability, and DTPA decomposing almost immediately.⁵⁵ The validity of acid dissociation experiments is questionable, as conditions such as these are never encountered in vivo (except for the stomach), but they are a quantifiable metric for measuring off-rate kinetics and further substantiates the place of DOTA as the current “gold standard” chelator for ¹¹¹In, ¹⁷⁷Lu, and ^86/90Y.⁵⁵

Although very little investigation of this isotope has been performed, DOTA is also the current chelator of choice for ⁴⁴Sc, although the requisite high temperature (90 °C) radiolabeling conditions are not optimal.^96–98 As ⁴⁴Sc has only recently become more popular in the literature, little in vivo work has been performed, and new chelators (preferably with ambient temperature radiolabeling properties) are of strong interest. Another isotope of recent interest for use with DOTA is the α-emitter ²²⁵Ac, which is a large actinide isotope that possesses no non-radioactive isotopologue, making study of its coordination chemistry difficult. The large macrocycles HEHA and PEPA (vide infra) had previously been used most extensively with ²²⁵Ac, but recently DOTA has been shown to have superior in vivo properties.⁹⁹ The long half-life of ²²⁵Ac (10.0 days) lends well to radioimmunotherapy (RIT), and so the high temperatures required for ²²⁵Ac radiolabeling with DOTA are very unfavorable for sensitive antibodies. The current method used for synthesizing ²²⁵Ac–DOTA–antibody conjugates is to radiolabel the BFC p-SCN-Bn-DOTA at 60 °C with ²²⁵Ac first, followed by antibody conjugation (thiourea coupling) and purification.^100,101 It is important to realize that the isothiocyanate functionality in the BFC p-SCN-Bn-DOTA is very sensitive and degrades rapidly under these conditions. A study comparing the therapeutic effects of ²²⁵Ac, ²¹³Bi, and ⁹⁰Y using an antibody vector demonstrated ²²⁵Ac to be the most effective, with renal toxicity from the daughters ²²¹Fr and ²¹³Bi being the most significant concern.¹⁰² A recent clinical trial in humans with ²²⁵Ac-DOTA-HuM195 (humanized anti-CD33 monoclonal antibody) has shown promise, with DOTA being the current “gold standard” for ²²⁵Ac.^100,103 A high denticity acyclic chelator (CN = 8–10) that could match the in vivo stability of DOTA and radiolabel at room temperature would be of great utility and would offer a more streamlined radiopharmaceutical preparation than the one outlined above for p-SCN-Bn-DOTA.

3.2 DOTA derivatives: CB-DO2A, 3p-C-DEPA, TCMC, and Oxo-DO3A

CB-DO2A has only been investigated with the radiometal ⁶⁴Cu for radiochemical use (Table 3).^68,144 An X-ray crystal structure of CB-DO2A with Ga³⁺ is available and shows a distorted octahedral coordination geometry, and acid stability experiments have been performed with Ga³⁺, revealing impressive acid inertness.¹⁴⁵ Although very little work has been done with CB-DO2A, studies with the non-bifunctional ⁶⁴Cu(CB-DO2A) have suggested that it had superior in vivo stability to DOTA and TETA, but inferior stability to CB-TE2A.¹³⁹ Further comparision of CB-DO2A to CB-TE2A, DOTA, and TETA revealed that CB-TE2A possessed superior acid and electrochemical inertness, which explains why DOTA and its cross-bridged derivative CB-DO2A have been replaced by CB-TE2A and are no longer a prominent subject of current research with ⁶⁴Cu.⁵⁶ Another interesting DOTA derivative is Oxo-DO3A, which is a heptadentate N₃O₄ macrocycle that has shown improved radiolabeling kinetics and stability with ⁶⁴Cu and ^67/68Ga compared to DOTA (Table 3). The p-NH₂-Bn-Oxo-DO3A derivative is shown in Table 3, which can be directly coupled to a peptide via standard peptide coupling reactions, or transformed to a benzyl-isothiocyanate.

Table 3 DOTA derivatives CB-DO2A, TCMC, 3p-C-DEPA, Oxo-DO3A, and bifunctional derivatives, highlighting relevant radiometal ions, radiolabeling conditions, thermodynamic stability constants (log K_ML), coordination geometry, and color-coded ranking

Chelator and common bifunctional derivatives	Radiometal ion		Radiolabeling conditions	log KML	Proposed geometry	Ref.
a Green “✓” = good/best match, orange “∼” = suitable match, or requires more evaluation but shows potential, red “✗” = poor/unstable match.
CB-DO2A, 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane, N4O2, CN = 6	^64Cu^2+		80 °C, 30–60 min, pH 5–7	—	Distorted octahedron	68, 144
	^67/68Ga^3+		—	—	Distorted octahedron	145
TCMC, 1,4,7,10-tetrakis(carbamoylmethyl)-l,4,7,10-tetraazacyclododecane, N4O4, CN = 8	^212Pb^2+		37 °C, 30–60 min, pH 5–6.5	>19	Square antiprismatic	138, 147, 148, 150, 153, 154
	p-SCN-Bn-TCMC^150
3p-C-DEPA, N5O5, CN = 10	^212/213Bi		25 °C, 5–10 min, pH 5.5	—	Square antiprismatic	152
	3p-C-DEPA-NCS^152			3p-C-DEPA = 2-[(carboxymethyl)][5-(4-nitrophenyl-1-[4,7,10-tris-(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]pentan-2-yl)-amino]acetic acid
p-NH2-Bn-Oxo-DO3A, N3O4, CN = 7	^64Cu^2+		25 °C, 10 min, pH 5.5	—	Distorted octahedron?	86, 87, 155, 156
	^67/68Ga^3+		25 °C, 10 min, pH 4–5	—	Distorted octahedron?	86, 157, 158

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Although DOTA has been used successfully with ²¹²Pb, its slow radiolabeling kinetics and stability properties were not ideal.¹⁴⁶ Replacement of the carboxylic acid donor arms of DOTA with amide arms has produced the chelator TCMC (Table 3), which to date is the best chelator available for ²¹²Pb.^147–149 Chappell et al. have shown TCMC to be superior to C-DOTA (Table 2) with ²¹²Pb due to improved radiolabeling kinetics and in vivo stability.^150,151 Although not optimal for ²¹²Pb, 3p-C-DEPA (Table 3) has been shown to be an excellent chelator for ^212/213Bi, with superior properties to C-DOTA.¹⁵² The DOTA derivative 3p-C-DEPA has demonstrated greatly improved radiolabeling kinetics with ^212/213Bi compared to DOTA, with comparable in vivo stability.¹⁵² 3p-C-DEPA can be considered to be one of the current “gold standards” for ^212/213Bi; however, the NOTA analogue 3p-C-NETA (vide infra) also looks very promising and has not been directly compared with 3p-C-DEPA, and so the superior of the two has yet to be identified.

3.3 TETA

TETA is an octadentate N₄O₄ macrocyclic chelator that has only been investigated with ⁶⁴Cu for radiopharmaceutical applications (Table 4). TETA is generally not used anymore, and has been superseded by newer generation chelators such as NOTA, CB-TE2A, and CB-TE1A1P/CB-TE2P (Table 4) that are more stable and kinetically inert in vivo. Copper is a difficult metal ion to harness, as it is quite labile, has active redox chemistry between Cu¹⁺/Cu²⁺in vivo, and has a fast water exchange rate of 2 × 10⁸ s⁻¹.^37,159 Copper(II) is a first row transition metal with a d⁹ electron configuration, is best used with hexadentate chelators that saturate its coordination sphere, and has a preference for borderline soft ligand donor atoms such as amines, imines, and thiols.^15,37 Despite being made obsolete in recent years, TETA has previously been used successfully for ⁶⁴Cu imaging with vectors like octreotide.^160,161 TETA can radiolabel with ⁶⁴Cu at room temperature, but it lacks kinetic inertness and overall stability in vivo. Surprisingly, the TETA derivative TE2A (Table 4) shows enhanced kinetic inertness, despite the fact that TE2A is merely a hexadentate derivative of TETA that is missing two carboxylic acid arms.¹⁶² This effect is enhanced even further when the two secondary amines of TE2A are methylated or cross-bridged by an ethylene unit (Table 4).^144,163 Unlike DOTA (cyclen-based), TETA (cyclam-based) has not been heavily investigated with any radiometals other than ⁶⁴Cu; however, some structural and physical data is available with other metal ions (Table 4).

Table 4 TETA, CB-TE2A and derivatives, and bifunctional derivatives, highlighting relevant radiometal ions, radiolabeling conditions, thermodynamic stability constants (log K_ML), coordination geometry, and color-coded ranking

Chelator and common bifunctional derivatives	Radiometal ion		Radiolabeling conditions	log KML	Proposed geometry	Ref.
a Green “✓” = good/best match, orange “∼” = suitable match, or requires more evaluation but shows potential, red “✗” = poor/unstable match.
TETA, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid, N4O4 CN = 8	^64Cu^2+		25 °C, 60 min, pH 5–7	21.9, 21.6	Distorted octahedron	160, 169
	^67/68Ga^3+		—	19.74 (pM 14.1)	Distorted octahedron	64
	^111In^3+		—	21.9 (pM 16.3)	Distorted octahedron?	64
	^177Lu^3+		—	15.3	Distorted dodecahedron?	170
	^86/90Y^3+		—	14.8	Distorted dodecahedron?	170
	BAT (C-TETA derivative)^171		p-NH2-Bn-TE3A^172		C-TETA (p-NO2-Bn-TETA)^173
CB-TE2A, 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane, N4O2 CN = 6	^64Cu^2+		95 °C, 60 min, pH 6–7	—	Distorted octahedron	68, 90, 106, 108, 164, 166–168, 174, 175
				^176
CB-TE1A1P^164,177	CB-TE2P^164,177		MM-TE2A^163	DM-TE2A^163	TE2A^162

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3.4 TE2A, CB-TE2A, CB-TE1A1P, CB-TE2P, MM-TE2A, DM-TE2A

The cyclam-based macrocycle TETA has spawned a large number of successful derivatives (Table 4). Despite the requisite harsh radiolabeling conditions (95 °C), CB-TE2A has become one of the premier ⁶⁴Cu chelators, having superior in vivo stability to TETA, TE2A, DOTA, NOTA, and CB-DO2A.¹⁴⁴ The stability gains from adding an ethylene cross bridge to TETA/TE2A are significant, despite the removal of two coordinating carboxylic acid arms, and a subsequent decrease in denticity from 8 to 6. In order to surmount the harsh radiolabeling conditions required for CB-TE2A, several derivatives of CB-TE2A have been synthesized. Improved radiolabeling kinetics have been achieved by replacement of one (CB-TE1A1P) or both (CB-TE2P) carboxylic acid arms with methylenephosphonate groups, with in vitro and in vivo stability being retained or enhanced compared to the native CB-TE2A (Table 4).^{144,164–168} Most importantly, the methylenephosphonate derivatives CB-TE1A1P and CB-TE2P can be radiolabeled with ⁶⁴Cu at room temperature, although relatively slowly. Another noteworthy set of derivatives were made by methylating one (MM-TE2A) or two (DM-TE2A) nitrogen atoms of TETA/TE2A, instead of linking them together with an ethylene bridge (Table 4).¹⁶³ Surprisingly, these methylated TE2A derivatives possessed similar radiolabeling kinetics and stability to CB-TE2A.¹⁶³ This observation suggests that the high stability of CB-TE2A is not a result of steric protection by the cage-like structure created by the cross-bridged ethylene unit, but instead by changing the electronic properties of the nitrogen atoms (secondary to tertiary amines) and their donor properties. Although CB-TE2A has been the most heavily investigated ligand of the above mentioned TETA derivatives, the new methylenephosphonate derivatives CB-TE1A1P and CB-TE2P show the most promise, as they appear to retain the stability of CB-TE2A, while having greatly enhanced radiolabeling kinetics.

3.5 Diamsar and derivatives

The radiometal ion ⁶⁴Cu²⁺, similar to ⁶⁸Ga³⁺, has been extremely popular in recent years due to its favorable positron emission (β⁺) properties for PET imaging and its intermediate half-life (12.7 hours), which is suitable for use with peptides, antibody fragments, and even whole antibodies. Unlike ⁶⁸Ga, ⁶⁴Cu also undergoes β⁻ emission, making it useful for therapy in addition to PET imaging. It follows, therefore, that there has been a strong interest in developing new and improved bifunctional chelators to optimize radiolabeling procedures and in vivo performance with isotopes of copper. In addition to the ubiquitous chelator NOTA (vide infra), new entrants such as CB-TE2A, CB-TE1A1P, CB-TE2P, MM-TE2A, and DM-TE2A have recently been determined to be excellent ⁶⁴Cu chelators (vide supra). The Sar family of chelators (hexamine sarcophagines) are hexaazamacrobicyclic cage type ligands, and include the ligands SarAr, SarAr-NCS, diamSar, AmBaSar, and BaBaSar (Table 5). One of the major benefits of these nitrogen rich chelators is that they can radiolabel with ⁶⁴Cu in only a few minutes (5–10 min) at room temperature, which is faster even than the recently devised ligands CB-TE1A1P and CB-TE2P (Table 4).^37,178–180 Of all the chelators discussed for ⁶⁴Cu, Sar derivatives have the fastest room temperature radiolabeling kinetics. In addition to fast kinetics, they demonstrate excellent in vivo stability, and strong resistance to acid dissociation in vitro.^178–181 One drawback to nitrogen rich N₆ chelators such as the Sar family is lipophilicity, as they contain little or no acid functionality to add negative charge, and as a result form cationic or neutral complexes with ⁶⁴Cu (depending on the Sar derivative). Because ⁶⁴Cu pairs exceptionally well with peptides, a lipophilic radiometal–chelator complex can have deleterious affects on biodistribution and tumor targeting properties by directing activity to the liver and digestive tract (depending on hydrophilicity of the selected peptide). The Sar derivative BaBaSar adds two carboxylic acid functional groups to the Sar scaffold, thereby augmenting hydrophilicity. Animal studies have been promising with the Sar family of chelators, but more work is required for further validation; furthermore, limited commercial availability and challenging synthesis may be a reason why widespread adoption has yet to occur.^37,178–181

Table 5 The copper chelators Diamsar, SarAr, AmBaSar, and BaBaSar, highlighting relevant radiometal ions, radiolabeling conditions, thermodynamic stability constants (log K_ML), coordination geometry, and color-coded ranking

Chelator and common bifunctional derivatives	Radiometal ion		Radiolabeling conditions	log KML	Proposed geometry	Ref.
a Green “✓” = good/best match, orange “∼” = suitable match, or requires more evaluation but shows potential, red “✗” = poor/unstable match.
Diamsar, N6, CN = 6	^64Cu^2+		25 °C, 5–30 min, pH 5.5		Distorted octahedron or trigonal prism	178–181
				1-N-(4-Aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine (SarAr)^178–182

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3.6 NOTA, NETA, and TACN-TM

NOTA is a hexadentate N₃O₃ chelator, and is one of the oldest and most successful chelators for use with ^67/68Ga and ⁶⁴Cu (Table 6). NOTA is generally considered to be the “gold standard” for Ga³⁺ chelation, possessing favorable radiolabeling conditions (RT, 30–60 minutes) and excellent in vivo stability.^{110,117,183,184} Of all the isotopes discussed in this review, ⁶⁸Ga is probably the most popular in recent years. ⁶⁸Ga has a very favorable positron emission (1880 keV, 90%) for PET imaging, and a short half-life (68 min) suitably matched for imaging with peptide vectors. The recent development of several ⁶⁸Ge/⁶⁸Ga-generator systems with shelf-lives of ∼9–12 months has propelled this radiometal into the spotlight of the international research scene.¹⁸⁵⁶⁷Ga is a longer-lived isotope of gallium that is suitable for SPECT imaging. Ga³⁺ is a hard acidic metal ion (pK_a 2.6) with an ionic radius of 62 pm (CN = 6), a preference for amine and oxygen donor atoms, and is ultimately a challenging metal ion to chelate because it has a strong affinity for hydroxide anions causing precipitation of gallium hydroxide (Ga(OH)₃) between pH 3–7.^62,159,186

Table 6 NOTA, NETA, TACN-TM, and bifunctional derivatives, highlighting relevant radiometal ions, radiolabeling conditions, thermodynamic stability constants (log K_ML), coordination geometry, and color-coded ranking

Chelator and common bifunctional derivatives	Radiometal ion		Radiolabeling conditions	log KML	Proposed geometry	Ref.
a Green “✓” = good/best match, orange “∼” = suitable match, or requires more evaluation but shows potential, red “✗” = poor/unstable match.
NOTA, 1,4,7-triazacyclononane-1,4,7-triacetic acid, CN = 6, N3O3	^64Cu^2+		25 °C, 30–60 min, pH 5.5–6.5	21.6	Distorted trigonal prism	187, 196
	^67/68Ga^3+		25 °C, 30–60 min, pH 4.0–5.5	31.0 (pM 26.4, 27.9)	Distorted octahedron	110, 117, 118, 183, 184, 197, 198
	^44/47Sc^3+		95 °C, 20–30 min, pH 4.0	16.5 (pM 19.2)	Distorted octahedron	98
	^111In^3+		60–95 °C, 20–30 min, pH 4.0–5.0	26.2 (pM 21.6)	Distorted octahedron	70, 117, 184, 199–201
p-SCN-Bn-NOTA(C-NOTA)^141,199	NODASA, R = NHS ester, amide^202			NODAGA, R = NHS ester, amide^200
NETA, {4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}-acetic acid, N4O4, CN = 8	^177Lu^3+		25 °C, 5 min, pH 4.5	—	Square antiprism?	127, 149, 190, 191
	^86/90Y^3+		25 °C, 5 min, pH 4.0	—	Square antiprism?	127, 189, 191
	^212/213Bi^3+		25 °C, 5 min, pH 4.0	—	Square antiprism?	149, 190, 191, 194
	^212Pb^2+		25 °C, 5 min, pH 4.0	—	Square antiprism?	191
NETA-monoamide^189	C-NE3TA-NCS^191		C-NETA-NCS^191		3p-C-NETA^127,193,194
TACN-TM, N,N′,N′′, tris(2-mercaptoethyl)1,4,7-triazacyclononane, N3S3 CN = 6	^67/68Ga^3+		25 °C, 10 min, degassed ethanol	34.2	Distorted octahedron	110, 195, 203, 204
	^111In^3+		25 °C, 10 min, degassed ethanol	36.1	Distorted octahedron	99, 176, 177, 183

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Because of its potential clinical utility, many new gallium chelators have been published in the last ∼5 years; however, most have not yet amassed the same amount of in vivo data as NOTA. NOTA has been shown to have superior radiolabeling properties and stability with ⁶⁴Cu when compared to common chelators such as DOTA, EDTA, DTPA, and TETA.^155,187 NOTA can radiolabel with ⁶⁴Cu at room temperature in 30–60 minutes, making it compatible with heat sensitive antibody vectors.¹⁸⁸ Although many new chelators like TRAP, AAZTA (DATA), H₂dedpa, CP256, and PCTA (vide infra) show great promise for use with ^67/68Ga in early experiments, due to commerical availability of BFC derivatives and widespread acceptance, NOTA is still currently the “gold standard” for ^67/68Ga. A similar story can be told for ⁶⁴Cu, where a plethora of new chelators, including the Sar family (e.g. SarAr, DiamSar), CB-TE2A, and various CB-TE2A derivatives (e.g. CB-TE1A1P, CB-TE2P, MM/DM-TE2A) appear to possess many superior properties, but NOTA is still the practical “gold standard” for ⁶⁴Cu.

The modified NOTA chelator NETA (Table 6) is an interesting derivative that shows promise with ^86/90Y, possessing fast radiolabeling kinetics similar to those of acyclic chelators (5–10 minutes, RT), as well as a high degree of stability and rigidity imparted by the macrocyclic framework.¹⁸⁹ A direct comparison between NETA and DOTA has demonstrated greatly enhanced radiolabeling kinetics for NETA with Y³⁺.¹⁸⁹ Biodistribution experiments performed with the ⁸⁶Y complexes of the non-bifunctional chelators NETA and DOTA have suggested that NETA had comparable clearance and stability properties to DOTA, even showing lower bone accumulation than DOTA.¹⁸⁹ NETA has been evaluated with other therapeutic isotopes for RIT, including ^203/212Pb, ^212/213Bi, and ¹⁷⁷Lu.^149,190,191 NETA and bifunctional derivatives C-NETA and C-NE3TA (Table 6) were found to be unstable with ^203/212Pb isotopes, but looked very stable with ^212/213Bi, ⁹⁰Y, and ¹⁷⁷Lu during a period of 11 days in blood serum.^191–193 Biodistribution studies of C-NETA complexes in healthy mice demonstrated excellent clearance and stability of the ^212/213Bi, ⁹⁰Y, and ¹⁷⁷Lu complexes, with the exception of high kidney uptake with the ^212/213Bi-C-NETA complex.¹⁹¹ Recent experiments with an isothiocyanate bearing derivative of C-NETA, 3p-C-NETA (Table 6) have demonstrated that ⁹⁰Y and ¹⁷⁷Lu radiolabeled immunoconjugates (trastuzumab) had very rapid room temperature radiolabeling kinetics, and excellent in vivo performance, with the potential to surpass DOTA and also DTPA analogues such as CHX-A′′-DTPA.¹²⁷ 3p-C-NETA has been further evaluated with ^212/213Bi for RIT applications, and trastuzumab immunoconjugates have been shown to exhibit rapid radiolabeling kinetics and excellent in vitro and in vivo stability, suggesting improved stability over C-NETA, which showed high kidney accumulation of ^212/213Bi.^191,194 It is interesting to note that these studies were actually performed with ^205/206Bi, as the longer half-lives (15.3/6.2 days, respectively) of these ^212/213Bi isotopologues are more amenable to extensive in vitro and in vivo study than are the short half-lives of ^212/213Bi.¹⁹⁴ Currently it is not clear if 3p-C-DEPA (Table 3) is superior to 3p-C-NETA (Table 6) for use with ^212/213Bi, and a direct comparison would be timely.

TACN-TM (Table 6) is an interesting thiol-based chelator, and shows extremely high thermodynamic stability constants (log K_ML) with Ga³⁺ and In³⁺ of 34.2 and 36.1, respectively.^{99,176,177,183} Another interesting thiol TACN derivative is TACN-HSB, which substitutes alkyl-thiols for thiophenol groups.¹⁹⁵ Despite the high thermodynamic stabilities, radiolabeling experiments required the use of degassed ethanol due to instability of the thiol groups of TACN-TM/TACN-HSB to air, and ultimately these ligands could not be used for in vivo applications.¹⁹⁵ For these reasons, no bifunctional derivatives have been synthesized of these thiol-based TACN/NOTA derivatives, and further study has not been pursued.

3.7 DTPA, 1B4M-DTPA, and CHX-A′′-DTPA

DTPA is one of the oldest and most pervasive acyclic chelators used in radiochemistry, and like most acyclic chelators it can be radiolabeled with many radiometal ions at room temperature in a matter of minutes (Table 7). As a first generation radiometal chelator, it suffers from stability issues in vivo with many radiometal ions and is universally not as stable as the macrocycles DOTA and NOTA, making its use obsolete in recent years.⁵⁶ DTPA has been successfully used as the BFC in the FDA-approved SPECT agent OctreoScan^TM (¹¹¹In-DTPA-octreotide), a somatostatin-targeting peptide-conjugate used for imaging neuroendocrine tumors.^205,206 DTPA has also been successfully used with radiometals such as ⁶⁴Cu, ¹¹¹In, ¹⁷⁷Lu, and ^86/90Y, but has been made redundant by more stable new chelators like DOTA, NOTA, and CHX-A′′-DTPA (Table 7).^56,161 The shortcomings of DTPA have been improved through design of novel derivatives, such as the DTPA derivatives 1B4M-DTPA (Tiuxetan) and CHX-A′′-DTPA.^56,207 1B4M-DTPA is a bifunctional DTPA derivative that contains a single methyl group on one of its ethylene backbones, and has been successfully incorporated into the FDA-approved ⁹⁰Y therapeutic immunoconjugate Zevalin (Table 7).^{207–209,210}

Table 7 DTPA, 1B4M, CHX-A′′-DTPA, and bifunctional derivatives, highlighting relevant radiometal ions, radiolabeling conditions, thermodynamic stability constants (log K_ML), coordination geometry, and color-coded ranking

Chelator and common bifunctional derivatives	Radiometal ion		Radiolabeling conditions	log KML	Proposed geometry	Ref.
a Green “✓” = good/best match, orange “∼” = suitable match, or requires more evaluation but shows potential, red “✗” = poor/unstable match.
DTPA, diethylenetriaminepentaacetic acid, N3O5, CN = 8	^64Cu^2+		40 °C, 60 min, pH 6.5	21.4	Distorted octahedron?	119, 234
	^67/68Ga^3+		25 °C, 30 min, pH 3.5	24.3, 25.5 (pM 20.2)	Distorted octahedron?	117, 119, 235
	^44/47Sc^3+		25 °C, 10 min, pH 6.0	—	Square antiprism?	16
	^111In^3+		25 °C, 5–10 min, pH 4.5–5.5	29.0 (pM 24.9)	Pentagonal bipyramid or square antiprism	117, 119, 236–238
	^177Lu^3+		25 °C, 10–20 min, pH 5.5	22.6	Square antiprism?	119, 131, 239
	^86/90Y^3+		25 °C, 10–20 min, pH 5.5	21.2, 22.0, 22.5	Monocapped square antiprism	55, 131, 132, 239
	^89Zr^4+		25 °C, 60 min, pH 7 (<0.1% yield)	35.8–36.9	Distorted dodecahedron	119, 240
	^212/213Bi^3+		25 °C, 10–20 min, pH 5	35.6	Square antiprism	119, 230–232
	p-SCN-Bn-1B-DTPA^211,241			p-SCN-Bn-1B4M-DTPA^224, 242, 243
CHX-A′′-DTPA, 2-(p-isothiocyanatobenzyl)-cyclohexyldiethylenetriaminepentaacetic acid, N3O5, CN = 8	^67/68Ga^3+		85 °C, 20 min, pH 5.5	—	Distorted octahedron?	217
	^111In^3+		25–60 °C, 30–60 min, pH 5.5	—	Square antiprism	217, 218, 224–229
	^177Lu^3+		37–75 °C, 30–60 min, pH 5–5.5	—	Square antiprism	54, 126, 128
	^86/90Y^3+		37–75 °C, 30–60 min, pH 5–5.5	—	Square antiprism	6, 7, 55, 56, 212–220
	^213Bi^3+		25 °C, 10–20 min, pH 5	—	Square antiprism	201, 221–223
	p-SCN-Bn-CHX-A’’-DTPA^56,212,244

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Although DTPA and DOTA are the most commonly investigated chelate systems for Y³⁺, the chelator CHX-A′′-DTPA (Table 7) shows significantly improved stability over DTPA; however, it is still generally considered to be less stable than DOTA.⁵⁶ The cyclohexyl backbone of CHX-A′′-DTPA makes the chelator more rigid and imposes a degree of preorganization on the metal ion binding site, enhancing kinetic inertness, but retarding radiolabeling kinetics compared to those of DTPA.^56,211 Due to the success of antibody vectors, developing acyclic chelators with fast radiometal ion coordination kinetics, as well as high stability and kinetic inertness comparable to that of macrocycles such as DOTA is an important goal. The work done towards developing CHX-A′′-DTPA was particularly interesting because of the 4 possible isomers of this chelator. The CHX-B′′-DTPA isomer was found to be much less stable than the CHX-A′′-DTPA isomer in vivo with ⁹⁰Y, despite in vitro stability assays suggesting they were very similar.^56,212 If CHX-DTPA were to be used as a racemic mixture it would result in significant decomposition of the less stable isomers and would lead to radiodemetallation in vivo, highlighting the importance of enantiopurity.^56,212 Different isomers of a BFC–radiometal complex can have different stabilities and off-rates (kinetic inertness), potentially leading to differential biodistributions.^42,59

Although CHX-A′′-DTPA has enhanced radiolabeling kinetics when compared to DOTA, both are still much slower than typical acyclic chelators such as DTPA and H₄octapa (Table 9), and often require mild heating (∼37–60 °C) and reaction times of 30–60 minutes to achieve reasonable yields. CHX-A′′-DTPA has been heavily investigated for use with many radiometals, including ^86/90Y,^{6,7,55,56,212–220177}Lu,^54,126,128 and ^212/213Bi,^{201,221–223} but work with ¹¹¹In has comparatively been limited.^{217,218,224–229} Studies that have been performed with ¹¹¹In(CHX-A′′-DTPA) conjugates have shown good in vivo results, but to our knowledge little work has been done comparing it with the “gold standard” ¹¹¹In chelator DOTA.²²⁸ A study comparing the in vivo behavior of the affibody conjugate ^114mIn-CHX-A′′-DTPA-ABD-(Z_HER2:342)₂ to ¹¹¹In-DOTA-ABD-(Z_HER2:342)₂ suggests that both chelators have comparable stability and performance, with CHX-A′′-DTPA exhibiting slightly higher tumor uptake, but also slightly higher non-target organ uptake (e.g. kidneys, liver, bone).^228114mIn is a notable γ-emitting isotope because it has identical chemistry to ¹¹¹In, but a longer 49.5-day half-life and interesting decay scheme (Table 1).²²⁸ When ^114mIn decays it emits a γ-ray for SPECT imaging, but the daughter nuclide ¹¹⁴In has a half-life of 72 seconds and emits high-energy (1989 keV) β⁻ particles useful for therapy.²²⁸ When the parent ^114mIn radiolabeled affibody internalizes into cells, it acts as an in vivo generator of ¹¹⁴In for intracellular delivery of therapeutic radioactivity (β⁻ particles) to cancer cells.²²⁸

Investigations with ^212/213Bi have found DTPA to possess fast radiolabeling kinetics, but poor in vivo stability, ultimately rendering it unusable.^{119,230–232} CHX-A′′-DTPA has been shown to possess enhanced stability with ^212/213Bi when compared to DTPA and 1B4M-DTPA, and even comparable stability to DOTA, while additionally possessing greatly enhanced radiolabeling kinetics (important for the short half-life of ^212/213Bi).^{201,221–223,231,233} The solid-state structure of the [Bi(CHX-A′′-DTPA)]²⁻ complex suggests that the partially pre-organized binding site offered by the rigid cyclohexyl backbone may contribute to the enhanced stability of the complex (also suggested as the cause for enhanced stability with other isotopes such as ^86/90Y and ¹⁷⁷Lu).²²¹ Although comparable to DOTA, CHX-A′′-DTPA is still considered to be inferior to 3p-C-NETA and 3p-C-DEPA for use with ^212/213Bi.

3.8 TRAP (PRP9) and NOPO

TRAP (PRP9) is a derivative of the macrocycle NOTA, wherein the traditional carboxylic acid arms have been replaced with phosphinic acid groups (Table 8).^{79–81,245–249} The most successful TRAP derivative, TRAP-Pr, contains an additional ethyl-carboxylate moiety extending distally from the phosphinic acid groups (Table 8).^{79–81,245–249} The most interesting property of the TRAP-Pr ligand is its improved apparent specificity for Ga³⁺ when compared to NOTA.^78,81 This phenomenon is expressed by the difference in thermodynamic stability constants (log K_ML) of TRAP and NOTA for competing metal ions such as Mg²⁺, Ca²⁺, Cu²⁺, and Zn²⁺,⁸¹ and by competitive radiolabeling experiments done in the presence of an excess of these other ions.⁷⁸ As a general rule, radiolabeling experiments are performed in strictly metal-free water and so the selectivity of TRAP-Pr for Ga³⁺ may not appear to be totally relevant, but it does suggest that transchelation by these competing metal ions in vivo should occur to a lesser extent than with NOTA. Additionally, as discussed in the introduction, the enhanced specificity of TRAP-Pr for ⁶⁸Ga over NOTA may be of benefit if trace-impurities are present in the stock radiometal solution (e.g.⁶⁸Ge/⁶⁸Ga generator eluent, or commercially supplied ⁶⁴Cu). A similar derivative to TRAP is NOPO, which is a triazacyclononane-triphospinate ligand that has a similar structure to TRAP-Pr, but with two terminal alcohol groups in place of carboxylic acids.^78,248,250 Like TRAP, NOPO has shown promising properties for ⁶⁴Cu and ⁶⁸Ga radiolabeling.^78,248,250

Table 8 Promising ^67/68Ga chelators TRAP (PRP9, TRAP-Pr), AAZTA (DATA), and bifunctional derivatives, highlighting relevant radiometal ions, radiolabeling conditions, thermodynamic stability constants (log K_ML), coordination geometry, and color-coded ranking

Chelator and common bifunctional derivatives	Radiometal ion		Radiolabeling conditions	log KML	Proposed geometry	Ref.
a Green “✓” = good/best match, orange “∼” = suitable match, or requires more evaluation but shows potential, red “✗” = poor/unstable match.
TRAP (PRP9, TRAP-Pr), 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid], N3O3 CN = 6 (+ distal carboxylates CN = 9?)	^67/68Ga^3+		95 °C, 5 min, pH 3.2	26.24	Distorted octahedron	79–81, 91, 245–249
				L = Linker, e.g. PEG8, PEG4, Glu, AHX, N3AHX. P = Peptide, e.g. RGD, DRG. NOPO ^78,248,257
AAZTA, and novel DATA derivatives, 1,4-bis (hydroxycarbonyl methyl)-6-[bis(hydroxylcarbonyl methyl)] amino-6-methyl perhydro-1,4-diazepine, N2O4 or N3O3, CN = 6	^67/68Ga^3+		25 °C, 1–5 min, pH 4–6.8	—	Distorted octahedron	253–256
	H3L^1			H3L^4

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The peptide conjugate TRAP(RGD)₃ was radiolabeled with ⁶⁸Ga in 5 minutes at 95 °C (HEPEs, pH 3.2), and despite the high reaction temperature was able to radiolabel at lower ligand concentrations than the corresponding DOTA or NOTA conjugates.^14,15 RGD (arginine–glycine–aspartic acid tripeptide) is a popular cyclic peptide vector that targets overexpression of integrin α_vβ₃ receptors on various types of cancer, and is commonly used as a proof-of-principle vector for studying new isotopes and new BFC.^{14,15,30,91,250,25168}Ga-TRAP(RGD)₃ demonstrated good in vivo tumor targeting properties, showing great promise for use in ⁶⁸Ga-based PET imaging agents;^14,15 however, a recent comparative biodistribution study between ⁶⁸Ga-TRAP(RGD)₃ and ⁶⁸Ga-NODAGA-RGD revealed higher uptake in several non-target organs for the TRAP-based agent.^79,91,246 Despite these apparent shortcomings, TRAP-Pr is a very promising ⁶⁸Ga chelator, which is a claim substantiated by the work of Dr Richard P. Baum at Zentralklinik Bad Berka in Germany, who has performed imaging experiments in human patients using ⁶⁸Ga-TRAP-peptide conjugates.²⁵²

3.9 AAZTA and derivatives (DATA)

The novel AAZTA derivatives H₃L¹ and H₃L⁴ are new ^67/68Ga-chelators that have shown improved radiolabeling and serum stability properties over the parent AAZTA chelator (Table 8). The parent AAZTA chelator was found to form multiple isomers with Ga³⁺, and so the derivatives H₃L¹ and H₃L⁴ were crafted such that one major isomer of the Ga³⁺ complex was kinetically trapped by attachment of bulky alkyl/aryl groups.^253–256 These AAZTA derivatives (now called DATA) are promising new Ga³⁺ chelators with extremely fast radiolabeling kinetics (1–5 minutes at RT) and good preliminary in vitro and in vivo stability results (as non-bifunctional chelators). These chelators are very recent, as most of this work has just been published in 2013, and so more extensive in vitro and in vivo experimentation will likely follow in the coming years. Additionally, no bifunctional derivatives (e.g. peptide conjugates) have been published to date, which will be required for proper evaluation and comparison in vivo to existing “gold standards” like NOTA.

3.10 H₂dedpa, H₄octapa, H₂azapa, and H₅decapa

This family of ligands has only been published over the previous 3 years and has been referred to as the “pa family”, as they are all crafted around central picolinic acid (“pa”) binding moieties (Table 9). This work originated in chelators made by Rodriguez-Blas and coworkers, originally purposed as contrast agents for magnetic resonance imaging (MRI) and luminescence.^258–267 H₂dedpa was the first chelator in this family to be investigated, with its acyclic hexadentate scaffold being ideal for ^67/68Ga, radiolabeling in less than 10 minutes at room temperature and forming a very symmetrical hexedentate coordination geometry (determined by solid-state X-ray structure).^{118,262,264,265,267}In vitro analysis of the [^67/68Ga(dedpa)]⁺ complex demonstrated excellent stability and resistance to transchelation by apo-transferrin and blood serum.¹¹⁸ The bifunctional derivative p-SCN-Bn-H₂dedpa has been synthesized and conjugated to the cyclic peptide RGD, radiolabeled with ⁶⁸Ga and ⁶⁴Cu, and has shown promising results for in vivo tumor targeting and PET imaging.^268,269 The H₂dedpa chelator has also been functionalized with lipophilic moieties, and the resulting cationic ⁶⁸Ga complexes have been investigated for cardiac perfusion imaging.²⁷⁰ Although preliminary work looks very promising for H₂dedpa, especially towards the production of kit-formulations with its very fast room temperature radiolabeling kinetics, more in vivo validation is required. As is the case with all new bifunctional chelators, the largest barrier to widespread adoption is commercial availability, as the synthesis and purification of most nitrogen and oxygen rich chelators are typically tedious and challenging.

Table 9 H₂dedpa, H₄octapa, H₂azapa, H₅decapa, and bifunctional derivatives, highlighting relevant radiometal ions, radiolabeling conditions, thermodynamic stability constants (log K_ML), coordination geometry, and color-coded ranking

Chelator and common bifunctional derivatives	Radiometal ion		Radiolabeling conditions	log KML	Proposed geometry	Ref.
a Green “✓” = good/best match, orange “∼” = suitable match, or requires more evaluation but shows potential, red “✗” = poor/unstable match.
H2dedpa, 1,2-[[6-(carboxy)-pyridin-2-yl]methylamino]ethane, N4O2 CN = 6	^64Cu^2+		25 °C, 5–10 min, pH 5.5	19.2 (pM = 18.5)	Distorted octahedron	269
	^67/68Ga^3+		25 °C, 5–10 min, pH 4.5	28.1 (pM = 27.4)	Distorted octahedron	118, 268, 270
	p-SCN-Bn-H2dedpa^118,268
H4octapa, N,N′-bis(6-carboxy-2-pyridylmethyl)ethylenediamine-N,N′-diacetic acid, N4O4 CN = 8	^111In^3+		25 °C, 5–10 min, pH 4.5	26.8 (pM = 26.5)	Square antiprism	83, 85
	^177Lu^3+		25 °C, 5–10 min, pH 4.5	20.1 (pM = 19.8)	Square antiprism	83
	p-SCN-Bn-H4octapa^83
H2azapa, N,N′-[1-benzyl-1,2,3-triazole-4-yl]methyl-N,N′-[6-(carboxy)pyridin-2-yl]-1,2-diaminoethane, N6O2 CN = 8 (benzyl groups as vector placeholder)	^64Cu^2+		25 °C, 5–10 min, pH 5.5	—	Distorted octahedron?	84
	^67/68Ga^3+		25 °C, 5–10 min, pH 4–4.5	—	Distorted octahedron?	84
	^111In^3+		25 °C, 5–10 min, pH 4.5	—	Square antiprism?	84
	^177Lu^3+		25 °C, 5–10 min, pH 4.5	—	Square antiprism?	84
H5decapa, N,N′′-[[6-(carboxy)pyridin-2-yl]methyl]diethylenetriamine-N,N′,N′′-triacetic Acid, N5O5 CN = 10	^111In^3+		25 °C, 5–10 min, pH 4.5	27.56 (pM = 23.1)	Square antiprism	83, 85

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H₂azapa was built on a variation of the click-to-chelate approach, where the peptide vector is conjugated to the chelator by click-chemistry, and the resultant triazole-rings are uniquely positioned so that they are capable of coordinating to radiometal ions in the inner-coordination sphere.^32,84,271 The triazole-containing H₂dedpa/H₄octapa derivative, H₂azapa, has been synthesized and evaluated with ⁶⁴Cu, ⁶⁸Ga, ¹¹¹In, and ¹⁷⁷Lu (Table 9).⁸⁴ Preliminary results were promising with ⁶⁴Cu, but in vitro stability assays suggest that complexes with ⁶⁸Ga, ¹¹¹In, and ¹⁷⁷Lu were unstable.⁸⁴ Due to the very lipophilic character of the neutral [Cu(azapa)] complex, in vivo evaluation revealed high liver and digestive tract uptake as expected, therefore more hydrophilic conjugates (e.g. peptide conjugates) must be synthesized and evaluated in the future.⁸⁴ The large decadentate derivative of H₄octapa, H₅decapa, was evaluated with ¹¹¹In in vitro and in vivo, and was found to be significantly less stable than were H₄octapa and DOTA (Table 9).^83,85

H₄octapa is a derivative of H₂dedpa, with an additional two carboxylic acid arms increasing the maximum denticity from 6 to 8 (Table 9).^{83,85,262,267} H₄octapa has recently been found to exhibit ideal properties for ¹¹¹In and ¹⁷⁷Lu radiochemistry, radiolabeling in quantitative yields at room temperature in less than 10–15 minutes.^83,85 Direct comparisons between H₄octapa and DOTA with both ¹¹¹In and ¹⁷⁷Lu have demonstrated similar in vivo properties and stability, with H₄octapa having greatly enhanced radiolabeling kinetics (significantly faster even than CHX-A′′-DTPA), suggesting that it may be a suitable alternative and improvement to DOTA.^83,85 Based on its excellent properties with ¹⁷⁷Lu, H₄octapa may also be a suitable match for the similar isotopes ^86/90Y, although no results have been published towards this goal thus far. Further preclinical work must be performed to validate H₄octapa as a suitable alternative to DOTA, although a direct comparison has been made with ¹¹¹In and ¹⁷⁷Lu in vitro and in vivo.^83,85

It appears that CHX-A′′-DTPA, C-NETA/3p-C-NETA, and H₄octapa are the best current alternatives to DOTA for fast radiolabeling kinetics and excellent in vivo stability with ¹¹¹In for SPECT imaging and dosimetry, and ¹⁷⁷Lu and ^86/90Y for therapeutic applications.^83,85,127 It is currently not clear how C-NETA/3p-C-NETA perform with ¹¹¹In because, to our knowledge, no studies have been published, and work with ¹¹¹In and CHX-A′′-DTPA is limited. If a SPECT imaging surrogate isotope such as ¹¹¹In is required for pre-therapy imaging and dosimetry, it appears that currently CHX-A′′-DTPA and H₄octapa are the most promising alternatives to DOTA.^83,85 A direct comparison between all of these chelators with ¹¹¹In, ¹⁷⁷Lu, and ^86/90Y in the same animal model at the same time would be of significant value.

3.11 HBED and SHBED

HBED and its derivative SHBED present an interesting example of chelator development, as the addition of an aromatic para-sulfonate group in SHBED to the phenol functionality of HBED serves to decrease the pK_a of the phenolic protons and alter their hard/soft metal-donor properties (Table 10). The original purpose of adding this aryl-sulfonate group to HBED was to increase its negative charge and hydrophilicity/solubility (fully deprotonated SHBED has a 6⁻ charge vs. 4⁻ for HBED), but the effect of changing the donor properties of the attached phenolic oxygen highlights an interesting option for tuning other chelators that contain aromatic donor groups.²⁷² Decreasing the pK_a of acidic functional groups in ligands can also help to improve radiolabeling efficiency: in this example by making the phenolic protons of SHBED more acidic and easier to deprotonate, and subsequently making SHBED a more effective ligand at lower pH. The bifunctional derivative HBED-CC has been conjugated to antibodies and was found to radiolabel much faster than NOTA, achieving a radiochemical yield (RCY) of 97% in under 5 minutes at room temperature, while also showing comparable in vivo performance to NOTA.^273,274 Although HBED has been around for several decades, limited work with ⁶⁸Ga has been performed, and other isotopes such as ⁶⁴Cu and ¹¹¹In have not shown optimal properties.^{117,273–276} HBED demonstrates that phenol and catechol donor groups are effective for Ga³⁺, but interestingly recent Ga³⁺ chelators such as H₂dedpa, TRAP, PCTA, AAZTA (DATA), and CP256 have not utilized them. Although an effective gallium chelator, HBED has received limited clinical use and has been supplanted in recent years by a plethora of new ligands.

Table 10 HBED, SHBED, BPCA, and bifunctional derivatives, highlighting relevant radiometal ions, radiolabeling conditions, thermodynamic stability constants (log K_ML), coordination geometry, and color-coded ranking

Chelator and common bifunctional derivatives	Radiometal ion		Radiolabeling conditions	log KML	Proposed geometry	Ref.
a Green “✓” = good/best match, orange “∼” = suitable match, or requires more evaluation but shows potential, red “✗” = poor/unstable match.
HBED, N,N′-bis(2-hydroxybenzyl)ethylenediamine-N,N′-diacetic acid, N2O4, CN = 6	^67/68Ga^3+		25 °C, 10–20 min, pH 4–4.5	38.5 (pM 28.6)	Distorted octahedron?	117, 273–276
	^44/47Sc^3+		25 °C, 10 min, pH 6.0	—	Square antiprism?	16
	^111In^3+		25 °C, 10–20 min, pH 4–7	27.9 (pM 17.9)	Distorted octahedron?	117, 275, 276
	HBED-CC^274,279			(HBED-CC)TFP^274
SHBED, N,N′-bis(2-hydroxy-5-sulfobenzyl)ethylenediamine-N,N′-diacetic acid, N2O4, CN = 6	^67/68Ga^3+		25 °C, 10–20 min, pH 4–4.5	37.5 (pM 28.3)	Distorted octahedron?	117, 272, 276
	^111In^3+		25 °C, 10–20 min, pH 4–7	29.4 (pM 20.6)	Distorted octahedron?	117, 272, 276
BPCA, N4O4, CN = 8	^111In^3+		25 °C, 60 min, pH 5	—	Square antiprism?	277, 278

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3.12 BPCA

BPCA is an interesting chelator that was published in 2010, which is based on a 2,2′-bipyridine backbone, and provides an octadentate N₄O₄ donor set (Table 10).^277,278 BPCA was conjugated to a novel cholecystokinin C-terminal tetrapeptide (CCK4), which targets tumors expressing the cholecystokinin receptor subtype 2 (CCK2R), and radiolabeled with ¹¹¹In in high RCY after 1 hour at room temperature. The novel peptide-conjugate BPCA–(Ahx)₂–CCK4 was evaluated in vitro by serum stability transchelation assays, and in vivo by biodistribution and planar scintigraphy experiments. The same (Ahx)₂–CCK4 conjugate was made with CHX-A′′-DTPA as an internal reference, and it was demonstrated that BPCA possessed superior stability to CHX-A′′-DTPA in serum (89% vs. 45% stable after 2.5 hours, respectively). Biodistribution and planar scintigraphic imaging studies showed that BPCA-based conjugates had higher tumor uptake, lower background organ uptake, and higher tumor/muscle ratios than CHX-A′′-DTPA, suggesting that BPCA is a very promising new chelator for ¹¹¹In. A study evaluating BPCA with ¹⁷⁷Lu and ^86/90Y would be of great interest.

3.13 CP256

CP256 and its bifunctional derivative YM103 are acyclic tripodal tris(hydroxypyridinone) ligands that can rapidly radiolabel with ⁶⁸Ga in 5 minutes at room temperature (Table 11).²⁸⁰ The maleimide derivative YM103 was conjugated to cysteine residues of the protein C2Ac, and in vivo experiments in normal healthy mice (no tumor models) showed rapid clearance through the kidneys with no observable decomposition after 1.5 hours.²⁸⁰ This new chelator was published less than 2 years ago, and further studies in tumor bearing mice will help to establish its potential utility. CP256 has an interesting acyclic tripodal design, similar to L3 (hydroxamate-based, Fig. 3), and most interestingly both chelators are oxygen-rich with O₆ donor sets, suggesting a potential untapped application as ⁸⁹Zr chelators (yet to be investigated, to our knowledge).

Table 11 The ^67/68Ga and ⁸⁹Zr chelators CP256, desferrioxamine (DFO), PCTA, H₆phospa, and bifunctional derivatives, highlighting relevant radiometal ions, radiolabeling conditions, thermodynamic stability constants (log K_ML), coordination geometry, and color-coded ranking

Chelator and common bifunctional derivatives	Radiometal ion		Radiolabeling conditions	log KML	Proposed geometry	Ref.
a Green “✓” = good/best match, orange “∼” = suitable match, or requires more evaluation but shows potential, red “✗” = poor/unstable match.
CP256, O6 CN = 6	^67/68Ga^3+		25 °C, 5 min, pH 6.5	—	Distorted octahedron	280
	Bifunctional derivative YM103^280			CP256 = 4-acetylamino-4-[2-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-carbamoyl]-ethyl]-heptanedioic acid bis-[(3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydro-pyridin-2-ylmethyl)-amide]
PCTA, 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid, N4O3 CN = 7	^64Cu^2+		25 °C, 5 min, pH 5.5	19.1	Distorted octahedron	87, 90, 214, 290
	^67/68Ga^3+		25 °C, 5–10 min, pH 4–5	—	Distorted octahedron	86, 290–292
	p-SCN-Bn-PCTA^214
DFO, desferrioxamine B, O6, CN = 6	^67/68Ga^3+		25 °C, 30 min, pH 3.5	28.6	Distorted octahedron?	235, 293
	^89Zr^4+		25 °C, 60 min, pH 7–7.3	—	Distorted octahedron?	51, 130, 240, 281, 283–288, 294–300
p-SCN-Bn-DFO^296		Bifunctional DFO derivatives^297,301
H6phospa, N,N′-(methylenephosphonate)-N,N′-[6-(methoxycarbonyl)pyridin-2-yl]methyl-1,2-diaminoethane, N4O4 CN = 8	^89Zr^4+		25 °C, 60 min, pH 7.4	—	Square antiprism?	289
	Bifunctional derivative p-SCN-Bn-H6phospa

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3.14 Desferrioxamine (DFO)

Desferrioxamine B (DFO) is a bacterial siderophore that natively binds Fe³⁺, and has also been used extensively with isotopes of gallium and zirconium (Table 11). DFO is the only competent ⁸⁹Zr chelator available for radiolabeling and in vivo applications.²⁸¹ Zr⁴⁺ is a highly charged, very hard metal ion with a relatively small ionic radius (84 and 89 pm for CN = 8 and 9, respectively),¹⁸⁶ that is prone to forming insoluble polynuclear hydroxide species in aqueous solution under non-acidic conditions, and subsequently is difficult to radiolabel effectively. DFO is thought to bind ⁸⁹Zr with its three hydroxamate groups in a hexadentate fashion, although no crystal structures have been obtained.²⁸² For many years the next best chelator for ⁸⁹Zr has been DTPA, which forms a thermodynamically stable complex with Zr⁴⁺ (log K_ML = 35.8–36.9), but studies have shown that radiolabeling with ⁸⁹Zr is inefficient and in vivo stability is exceptionally poor.¹¹⁹ A DTPA–antibody conjugate of Zevalin was radiolabeled with ⁸⁹Zr, and radiochemical yields obtained were <0.1% after 1 hour at room temperature;²⁴⁰ in contrast, DFO can radiolabel with ⁸⁹Zr in quantitative yields (>99%) after 1 hour. The new chelator H₆phospa has recently been studied with ⁸⁹Zr, and has shown greatly improved radiolabeling performance relative to DTPA, but still inferior to DFO (vide infra).

No FDA-approved radiopharmaceuticals currently utilize ⁸⁹Zr, although a number of ⁸⁹Zr–DFO–antibody conjugates are in clinical trials.²⁰⁸⁸⁹Zr has a long half life (78.5 hours), making it ideally paired with antibody vectors, as the biological half-life of an antibody is on the order of 2–3 weeks.³⁸⁸⁹Zr–DFO–Zevalin was the first ⁸⁹Zr antibody conjugate imaged in humans, and was shown to be a suitable PET surrogate for ⁹⁰Y-Zevalin dosimetry.²⁸³ A number of other studies have been performed using ⁸⁹Zr-DFO-antibody conjugates with success, such as ⁸⁹Zr-DFO-U36 (anti-CD446 chimeric mAb),^208,28489Zr-DFO-bevacizumab,^208,28589Zr-DFO-J591,²⁸¹⁸⁹Zr-DFO-TRC105,²⁸⁶ and ⁸⁹Zr-DFO-trastuzumab.^208,287,288

The high 4+ charge makes ⁸⁹Zr challenging to incorporate into BFC systems while still retaining bioequivalence with other common 3+ cationic metal ions (e.g. In³⁺, Ga³⁺, Y³⁺, Lu³⁺), because the chelate–radiometal charge and polarity is different. Evaluating the stability of a potential BFC for ⁸⁹Zr can be done in vivo, because ⁸⁹Zr that is lost from a BFC typically localizes in bone, as demonstrated by the highly unstable ⁸⁹Zr-DOTA- and ⁸⁹Zr-DTPA-based antibody conjugates with cetuximab that showed significant ⁸⁹Zr accretion in the thighbone 72 hours post injection.¹³⁰⁸⁹Zr-chloride and ⁸⁹Zr-oxalate have also been injected directly into mice, with ⁸⁹Zr-chloride forming colloids and accumulating in the liver, and the weakly chelated ⁸⁹Zr-oxalate demonstrating rapid bone uptake.²⁸¹ Although DFO is an excellent ⁸⁹Zr chelator, some decomposition can be observed over time in vivo as ⁸⁹Zr slowly accumulates in bone.^27,51 The design of novel chelators for ⁸⁹Zr with improved solubility, in vivo stability, and chelation properties would be timely, considering there is currently only one option (DFO). Based on the success of DFO, it would appear that oxygen-rich donors are most suitable for ⁸⁹Zr chelation, with O₆–O₈ coordination being preferred, and donor groups including hydroxamates, carboxylates, carbonyls, catechols, and hydroxypyridinones being logical choices.

3.15 H₆phospa

Developing new chelating agents for ⁸⁹Zr is currently of great interest, as the only chelator available that can radiolabel ⁸⁹Zr with any level of proficiency is DFO. As discussed in Section 3.14, the best alternative chelator to DFO for ⁸⁹Zr radiolabeling is DTPA; however, with meager radiochemical yields of <0.1% after 1 hour at room temperature and poor in vivo stability, DTPA is not a viable alternative to DFO.²⁴⁰ DFO can radiolabel with ⁸⁹Zr in quantitative yields (>99%) after 1 hour at room temperature, and demonstrates imperfect but acceptable stability in vivo, and no acceptable alternatives have been published to date. The acyclic chelator H₆phospa (Table 11),^264,265 and the bifunctional derivative p-SCN-Bn-H₆phospa are methylenephosphonate derivatives of H₄octapa (Table 9) that have been recently studied with ⁸⁹Zr.²⁸⁹ The antibody conjugate H₆phospa-trastuzumab was able to achieve radiochemical yields of ∼8% with ⁸⁹Zr after 1 hour at room temperature (PBS, pH 7.4).²⁸⁹ This work was compared to previous attempts to radiolabel H₄octapa-trastuzumab with ⁸⁹Zr, which performed similarly to DTPA and exhibited essentially no radiolabeling after 1 hour.²⁸⁹ These results demonstrate that replacing the carboxylic acid arms of H₄octapa with methylenephosphonate arms in H₆phospa improved radiolabeling kinetics with ⁸⁹Zr, suggesting that methylenephosphonate groups are more suitable than carboxylic acid groups for chelating ⁸⁹Zr.²⁸⁹ Although a RCY of ∼8% is insufficient to supplant DFO as the “gold standard” chelator for radiolabeling with ⁸⁹Zr, it is a significant improvement over DTPA and H₄octapa, and to our knowledge is the highest ⁸⁹Zr radiolabeling yield behind DFO to be published.

3.16 PCTA

The heptadentate macrocyclic chelator PCTA was originally synthesized by Sherry and coworkers as a potential MRI contrast agent (Table 11).²⁹⁰ PCTA has been recently re-purposed and evaluated with ⁶⁸Ga and ⁶⁴Cu, and has been shown to possess much faster radiolabeling kinetics than DOTA (5–10 min, RT).⁸⁶ The serum stability of the ^67/68Ga–PCTA complex was found to be superior to DOTA, and comparable to NOTA.⁸⁶ Additionally, the biodistribution profile of the non-bifunctional ⁶⁸Ga–PCTA revealed lower kidney retention than ⁶⁸Ga–NOTA, showing potential improvement over NOTA for use in peptide conjugates.⁸⁶ Comparisons of RGD conjugates of the bifunctional derivatives of both PCTA and NOTA have demonstrated excellent in vivo stability and comparable biodistribution profiles, with the PCTA-based agent having lower kidney uptake than its NOTA counterpart.²⁹¹ PCTA has also been investigated with ⁶⁴Cu, showing greater radiolabeling kinetics and yields to DOTA, and superior in vitro and in vivo stability.⁷⁵ PCTA has only recently been investigated, but further work may show it to be an excellent chelator for copper and gallium-based radiopharmaceuticals.

3.17 HEHA and PEPA

HEHA is a large 18-membered, 12 coordinate, macrocyclic chelator, and PEPA is a structurally similar 10 coordinate derivative (Table 12). Both HEHA and PEPA have primarily been investigated for ²²⁵Ac complexation and RIT; preliminary radiolabeling and in vitro/in vivo stability experiments with ²²⁵Ac had suggested that HEHA was superior to DOTA and PEPA.²²⁴ The antibody conjugate HEHA-MAb-201B was radiolabeled with ²²⁵Ac and used to treat lung tumors in mice, and although effective at delivering large doses of ²²⁵Ac to tumors, high radiotoxicity from decay daughter isotopes resulted in death.³⁰² More recently, using different in vitro experiments (e.g. cation exchange resin challenge) and different in vivo targets, DOTA has been shown to be the most suitable ²²⁵Ac chelator.^101,103,303 A recent clinical trial with ²²⁵Ac-DOTA-HuM195 (humanized anti-CD33 monoclonal antibody) in humans has shown promise.^100,103 PEPA has also been investigated for use with ^212/213Bi for therapy applications, but was found to be unsuitable.³⁰⁴ α-emitting isotopes are currently of very high interest and potential impact, due to their effectiveness at killing cancer cells when they are tightly chelate-bound and safely delivered to their targets.^{3,134,149,151,210,303} α-particles travel a very short distance (μm range, compared to mm range for β⁻ particles) and have high linear energy transfer values (LET), meaning they deposit huge amounts of energy over a very short distance, making them very effective at treating various cancers when properly directed, but also potentially very toxic.^{3,134,149,151,210,303} Development of new chelators for use with α-emitting isotopes is currently of high impact in the field of BFC.

Table 12 The ²²⁵Ac chelators HEHA, PEPA, and bifunctional derivatives, highlighting relevant radiometal ions, radiolabeling conditions, thermodynamic stability constants (log K_ML), coordination geometry, and color-coded ranking

Chelator and common bifunctional derivatives	Radiometal ion		Radiolabeling conditions	log KML	Proposed geometry	Ref.
a Green “✓” = good/best match, orange “∼” = suitable match, or requires more evaluation but shows potential, red “✗” = poor/unstable match.
HEHA, 1,4,7,10,13,16-hexaazacyclohexadecane-N,N′,N′′,N′′′,N′′′′,N′′′′′-hexaacetic acid, N6O6, CN = 12	^225Ac^3+		37–40 °C, 30 min, pH 5.8–7	—	?	99, 101, 103, 303–305
	p-SCN-Bn-HEHA (C-HEHA)^99
PEPA, 1,4,7,10,13-pentaazacyclopentadecane-N,N′,N′′,N′′′,N′′′′-pentaacetic acid, N5O5, CN = 10	^212/213Bi^3+		25 °C, 15 min, pH 5–5.5	—	?	304
	^225Ac^3+		37–40 °C, 30-60 min, pH 5.8–7	—	?	99
	p-SCN-Bn-PEPA (C-PEPA)^304

---

4. A brief look at less-developed chelators

A large number of chelators have been used transiently over the years for study and application with a variety of radiometals, but have not garnered very much interest from the radiochemistry community, have not been sufficiently developed to date, or have lacked a required level of proficiency (e.g. reaction kinetics, RCY, stability) for mainstream use. Additionally, a chelator may have shown great promise for use with a radiometal, but a suitable synthetic route to a bifunctional derivative may never have been published. Shown in Fig. 4 is a selection of chelators that have not been discussed here, but still may be of interest or of use to some researchers. These chelators may not have been found to be a suitable match to any of the current gamut of available radiometal ions discussed here, but production of more exotic radiometals in the future may bring them into relevance. Inspiration may also be drawn from the chemical structures, donor-atom types, connectivity, or geometries of these chelators, and potentially used towards new and novel chelators.

Fig. 4 A selection of less-discussed chelators with potential applications in radiometal chemistry, including NEC-SP,³⁰⁶ L1 (TACN-HSB, tris(2-mercaptobenzyl)amine),³⁰⁷ BAT-TM,^308,309 EC,^117,310 SBAD,³¹¹ BAPEN,^312–314 TACHPYR,^315–317 L2 (9-hydroxy-2,4-dipyridin-2-yl-3,7-bis(pyridin-2-ylmethyl)-3,7-diazabicyclo-[3.3.1]nonane-1,5-dicarboxylic acid),³¹⁸ DiP-LICAM,^319,320 and the hydroxamate-based L3.³²¹

4.1 Conclusions

After examining the large number of highly competent radiometal chelators displayed in this review, some researchers may be daunted or even disheartened at the idea of creating new scaffolds with the existence of so many chelators that already work “well enough”. Radiometal chemistry teaches us that the intricate relationships amongst radiometal ion, chelator, linker, biological vector (e.g. peptide, antibody, antibody fragment, nanoparticle), and animal/tumor models are surprisingly complicated and only superficially understood. In order to optimally tune the properties of radiometal-based radiopharmaceuticals, a large variety of different tools (e.g. chelators, linkers, vectors) are crucial to have available so that the physical properties of an agent can be easily modified. Factors such as the charge, polarity, denticity, donor atom type (e.g. N, O, S), and kinetics (e.g. macrocyclic vs. acyclic) must be modular in order to optimize in vivo behavior of a radiopharmaceutical, and this requires the availability of many different bifunctional chelators. The synthetic canon of radiopharmaceutical components will always have space for new innovation and curiosity so that radioactive imaging agents and therapeutics can be continually improved.

Current directions in radiochemistry and nuclear medicine highlight the importance of PET imaging, and subsequently the significance of optimal utilization of a growing number of β⁺ emitting radiometal ions. Promising new PET isotopes such as ⁴⁴Sc and ⁸⁹Zr currently have poorly elaborated chelate chemistry, and moving forward the development of fast-radiolabeling and exceptionally stable chelators for these isotopes will be important. ⁶⁸Ga is perhaps the most promising of all isotopes discussed here, primarily due to its highly portable and long-lived generator system. To properly utilize ⁶⁸Ga and translate it to the clinic, the wide-range of excellent ⁶⁸Ga chelators that are currently under investigation must be transformed into viable imaging agents to provide useful diagnostic tools to the medical community. α-emitting isotopes are also currently of strong interest, as they are extremely effective, when targeted, at site-specifically delivering therapeutic doses of radioactivity to a variety of cancers. The caveat of α-emitters is their potentially fatal toxicity, and therefore robust chelate chemistry is of utmost importance for the continued development of therapeutic agents based on isotopes such as ²²⁵Ac, ^212/213Bi, and ²¹²Pb.

Acknowledgements

We acknowledge NSERC for CGS-M/CGS-D fellowships (E.W.P.) and many years of research support (C.O.), as well as the University of British Columbia for a 4YF fellowship (E.W.P.). C.O. acknowledges the Canada Council for the Arts for a Killam Research Fellowship (2011–2013), the University of Canterbury for a Visiting Erskine Fellowship (2013), and the Alexander von Humboldt Foundation for a Research Award, as well as Prof. Dr Peter Comba and his research group in Heidelberg for hospitality and interesting discussions. We also thank Caterina F. Ramogida for thoughtful editing.

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