Catechol-based functionalizable ligands for gallium-68 positron emission tomography imaging

Four tris-bidentate catecholamide (CAM) ligands were synthesized, characterized, and evaluated as ligands for radiolabeling of gallium-68 for positron emission tomography (PET). Three of those ligands, 2,2-Glu-CAM, 3,3-Glu-CAM, and TREN-bisGlyGlu-CAM, incorporate ligand caps that contain a pendant carboxylic group for further conjugation to targeting moieties. The acyclic ligands all exhibited high (>80%) radiolabeling yields after short reaction times (<10 min) at room temperature, a distinct advantage over macrocyclic analogues that display slower kinetics. The stabilities of the four GaIII complexes are comparable to or higher than those of other acyclic ligands used for gallium-68 PET imaging, such as desferrioxamine, with pGa values ranging from 21 to >24, although the functionalizable ligands are less stable than the parent GaIII-TREN-CAM. In vivo imaging studies and ex vivo pharmacokinetic and biodistribution studies indicate that the parent [68Ga]Ga-TREN-CAM is stable in vivo but is rapidly cleared in <15 min, probably via a renal pathway. The rapid and mild radiolabeling conditions, high radiolabeling yields, and high stability in human serum (>95%) render TREN-bisGlyGlu-CAM a promising candidate for gallium-68 chelation.