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

Dalton Transactions Pub Date: 2014-03-14 DOI: 10.1039/C4DT00239C

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 KML) 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.

Graphical abstract: Modular syntheses of H4octapa and H2dedpa, and yttrium coordination chemistry relevant to 86Y/90Y radiopharmaceuticals
Recommended Literature