Modular syntheses of H4octapa and H2dedpa, and yttrium coordination chemistry relevant to 86Y/90Y radiopharmaceuticals

Abstract

The ligands H₂dedpa, H₄octapa, p-SCN-Bn-H₂dedpa, and p-SCN-Bn-H₄octapa were synthesized using a new protection chemistry approach, with labile tert-butyl esters replacing the previously used methyl esters as protecting groups for picolinic acid moieties. Additionally, the ligands H₂dedpa and p-SCN-Bn-H₂dedpa were synthesized using nosyl protection chemistry for the first time. The use of tert-butyl esters allows for deprotection at room temperature in trifluoroacetic acid (TFA), which compares favorably to the harsh conditions of refluxing HCl (6 M) or LiOH that were previously required for methyl ester cleavage. H₄octapa has recently been shown to be a very promising ¹¹¹In and ¹⁷⁷Lu ligand for radiopharmaceutical applications; therefore, coordination chemistry studies with Y³⁺ are described to assess its potential for use with ⁸⁶Y/⁹⁰Y. The solution chemistry of H₄octapa with Y³⁺ is shown to be suitable via solution NMR studies of the [Y(octapa)]⁻ complex and density functional theory (DFT) calculations of the predicted structure, suggesting properties similar to those of the analogous In³⁺ and Lu³⁺ complexes. The molecular electrostatic potential (MEP) was mapped onto the molecular surface of the DFT-calculated coordination structures, suggesting very similar and even charge distributions between both the Lu³⁺ and Y³⁺ complexes of octapa⁴⁻, and coordinate structures between 8 (ligand only) and 9 (ligand and one H₂O). Potentiometric titrations determined H₄octapa to have a formation constant (log K_ML) with Y³⁺ of 18.3 ± 0.1, revealing high thermodynamic stability. This preliminary work suggests that H₄octapa may be a competent ligand for future ⁸⁶Y/⁹⁰Y radiopharmaceutical applications.