Exploring the Chemistry of H2DEDPA Derivatives for [nat/68Ga]Ga3+ Complexation

Abstract

[Abstract] We report a detailed study of the coordination chemistry of acyclic hexadentate H2DEDPA derivatives towards [nat/68Ga]Ga3+ (H2DEDPA = 6,6′-((ethane-1,2-diylbis(azanediyl))bis(methylene))dipicolinic acid). Three structural modifications were considered, involving the substitution of the central ethylene spacer of H2DEDPA by 1,2-cyclohexyldiamine, 1,2-cyclopentyldiamine or 1,3-cyclobutyldiamine linkers, affording chelators H2CHXDEDPA, H2CpDEDPA and H2CBuDEDPA, respectively. The X-ray structures of [Ga(CpDEDPA)](PF6)·3H2O and [Ga(CBuDEDPA)](ClO4)·H2O evidence hexadentate binding of the ligands to Ga3+, which displays a distorted octahedral coordination environment. Solution structures compare well to those observed in the solid state, as demonstrated by NMR studies and DFT calculations. The stability constants of the complexes were determined using spectrophotometric titrations (25 °C, 1 M NaCl), affording log KGaL values of 24.94, 21.90 and 19.50 for the complexes of CHXDEDPA2−, CpDEDPA2− and CBuDEDPA2−, respectively. Both CHXDEDPA2− and CpDEDPA2− can be quantitatively radiolabeled with 10 nmol [68Ga]Ga3+ at room temperature (0.5 M ammonium acetate at pH 5) with no significant difference between 15, 30 and 60 min labeling time, whereas CBuDEDPA2− produced a < 50 % radiochemical yield. The radiolabeled complexes of CHXDEDPA2− and CpDEDPA2− showed high stability in PBS buffer and in the presence of 1000 equivalents of DTPA5−, with CpDEDPA2− providing slightly better results. However, in vivo PET imaging and biodistribution studies evidence dissociation of the CpDEDPA2− complex, while the [68Ga][Ga(CHXDEDPA)]+ complex remains stable and demonstrates mixed, renal and hepatic clearance.