Synthesis and characterization of lipophilic cationic Ga(iii) complexes based on the H2CHXdedpa and H2dedpa ligands and their 67/68Ga radiolabeling studies

Abstract

⁶⁸ Ga is an attractive isotope for incorporation into a positron-emission tomography (PET) imaging agent, and is finding use as an alternative generator-produced isotope to ^99mTc particularly in imaging of myocardial perfusion. We have synthesized six new chelating ligands based on our previously reported H₂dedpa and H₂CHXdedpa scaffolds (CHX = cyclohexyl, H₂dedpa = 1,2-[[carboxypyridin-2-yl]methylamino]ethane). These ligands are designed to incorporate several lipophilic appendages at the secondary nitrogens, and upon coordination to ⁶⁸Ga(III) will form lipophilic, cationic complexes designed to mimic the properties of other clinically relevant myocardial perfusion imaging agents. The non-radioactive Ga(III) complexes were prepared and characterized by NMR spectroscopy; each ligand retained its predicted hexadentate N₄O₂ binding to Ga(III). The radiolabeling properties of the six ligands were assessed using the longer-lived ⁶⁸Ga surrogate, ⁶⁷Ga. The absence of ‘free’ uncomplexed ⁶⁷Ga in the HPLC radio-chromatograms indicated >99% radiochemical yields (10 minutes at ambient temperature, ligand concentrations of 10⁻⁴ M). However, the N,N′-benzyl functionalized derivatives displayed multiple peaks corresponding to the presence of additional ⁶⁷Ga-complexes which complicated further study. Selected ⁶⁷Ga-CHXdedpa complexes were tested for in vitro stability against the metal-binding protein apo-transferrin, and were found to be sufficiently stable (>80%) in a 2 h challenge assay, suggesting that alternative N,N′-alkylated derivatives which introduce more lipophilic character will be of interest in future studies.