New Ga derivatives of the H2dedpa scaffold with improved clearance and persistent heart uptake

Recent advances in positron emission tomography (PET)/computed tomography have fueled the development of new PET-isotope-based agents for myocardial perfusion imaging. 68Ga, a generator-produced PET isotope, is an attractive radionuclide for developing a 68Ga-based cardiac imaging agent. We have synthesized seven new chelate systems based on our previously reported 1,2-[{6-(carboxylato-)pyridin-2-yl}methylamino]ethane (H2dedpa) scaffold. These ligands form lipophilic, cationic complexes upon coordination of 67/68Ga(III) under mild, direct labeling conditions within 10 min at room temperature. The corresponding cold complexes were also synthesized, and the solid-state structure of one of the complexes, [Ga(19)][ClO4], was determined. All compounds were investigated for in vitro stability against transferrin, and log P values were determined. In vivo biodistribution studies in mice showed that four of the seven investigated complexes provided greatly improved blood, lung and kidney clearance compared to previously reported derivatives. Two complexes with log P>1.1 exhibited persistent heart uptake over the course of 2 h above 1% ID/g.