1 research outputs found
Gallium Complexation, Stability, and Bioconjugation of 1,4,7-Triazacyclononane Derived Chelators with Azaheterocyclic Arms
We have recently introduced a 1,4,7-triazacyclononane
(TACN) based chelating system with additional five-membered azaheterocyclic
substituents for complexation of radioactive Cu<sup>2+</sup> ions.
In this work, we investigated the complexation properties of these
novel chelators with Ga<sup>3+</sup>. In labeling experiments, we
could show that the penta- and hexadentate imidazole derivatives NODIA-Me <b>4</b> and NOTI-Me <b>1</b> can be labeled with <sup>68</sup>Ga in specific activities up to ∼30 MBq nmol<sup>–1</sup>, while the corresponding thiazole derivative NOTThia <b>2</b> did not label satisfactorily under identical conditions. NMR studies
on the Ga complexes of <b>1</b> and the model compound NODIA-Me-NH-Me <b>5</b> revealed formation of rigid 1:1 chelates with a slow macrocyclic
interconversion and inert Ga–N bonds to the methylimidazole
residues on the NMR time scale. The TACN-derived bifunctional chelator
NODIA-Me was furthermore conjugated to a prostate-specific membrane
antigen (PSMA) targeting moiety to give the corresponding bioconjugate
NODIA-Me-PSMA <b>7</b>. Serum stability and ligand challenge
experiments of <sup>68</sup>Ga-<b>7</b> confirmed formation
of a stable complex for up to 4 h. The remaining coordination site
of five-coordinate Ga complexes was found to be occupied by monodentate
ligands including hydroxide and chloride anions depending on the conditions.
According to density functional theory calculations, coordination
of monodentate ligands as well as of the amide group for the bioconjugated
ligand are energetically plausible. Finally, the labeled bioconjugate <sup>68</sup>Ga-<b>7</b> exhibited rapid renal clearance in biodistribution
studies performed by small animal PET imaging with no indication of
transchelation/demetalation in vivo. Altogether, our results provide
strong evidence for a stable Ga complexation of our novel TACN-based
chelators bearing imidazole arms. Despite the formation of two complexes
incorporating different monodentate ligands in vitro, the imidazole
type ligands show promise as chelating agents for the future development
of gallium based radiopharmaceuticals