Exploring the chemistry of HDEDPA derivatives for [Ga]Ga complexation.

We report a detailed study of the coordination chemistry of acyclic hexadentate HDEDPA derivatives towards [Ga]Ga (HDEDPA = 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 HDEDPA by 1,2-cyclohexyldiamine, 1,2-cyclopentyldiamine or 1,3-cyclobutyldiamine linkers, affording chelators HCHXDEDPA, HCpDEDPA and HCBuDEDPA, respectively. The X-ray structures of Ga(CpDEDPA)·3HO and Ga(CBuDEDPA)·HO evidence hexadentate binding of the ligands to Ga, 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 K values of 24.94, 21.90 and 19.50 for the complexes of CHXDEDPA, CpDEDPA and CBuDEDPA, respectively. Both CHXDEDPA and CpDEDPA can be quantitatively radiolabeled with 10 nmol [Ga]Ga at room temperature (0.5 M ammonium acetate at pH 5) with no significant difference between 15, 30 and 60 min labeling time, whereas CBuDEDPA produced a < 50 % radiochemical yield. The radiolabeled complexes of CHXDEDPA and CpDEDPA showed high stability in PBS buffer and in the presence of 1000 equivalents of DTPA, with CpDEDPA providing slightly better results. However, in vivo PET imaging and biodistribution studies evidence dissociation of the CpDEDPA complex, while the [Ga][Ga(CHXDEDPA)] complex remains stable and demonstrates mixed, renal and hepatic clearance.