Phosphinic acid functionalized polyazacycloalkane chelators for radiodiagnostics and radiotherapeutics: Unique characteristics and applications

Given the wide application of positron emission tomography (PET), positron-emitting metal radionuclides have received much attention recently. Of these, gallium-68 has become particularly popular, as it is the only PET nuclide commercially available from radionuclide generators, therefore allowing local production of PET radiotracers independent of an on-site cyclotron. Hence, interest in optimized bifunctional chelators for the elaboration of ⁶⁸Ga-labeled bioconjugates has been rekindled as well, resulting in the development of improved triazacyclononane-triphosphinate (TRAP) ligand structures. The most remarkable features of these ligands are unparalleled selectivity for Ga^III, rapid Ga^III complexation kinetics, extraordinarily high thermodynamic stability, and kinetic inertness of the respective Ga^III chelates. As a result, TRAP chelators exhibit very favorable ⁶⁸Ga-labeling properties. Based on the scaffolds NOPO (1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid]) and TRAP-Pr, tailored for convenient preparation of ⁶⁸Ga-labeled monomeric and multimeric bioconjugates, a variety of novel ⁶⁸Ga radiopharmaceuticals have been synthesized. These include bisphosphonates, somatostatin receptor ligands, prostate-specific membrane antigen (PSMA)-targeting peptides, and cyclic RGD pentapeptides, for in vivo PET imaging of bone, neuroendocrine tumors, prostate cancer, and integrin expression, respectively. Furthermore, TRAP-based ⁶⁸Ga-labeled gadolinium(III) complexes have been proposed as bimodal probes for PET/MRI, and a cyclen-based analogue of TRAP-Pr has been suggested for the elaboration of targeted radiotherapeutics comprising radiolanthanide ions. Thus, polyazacycloalkane-based polyphosphinic acid chelators are a powerful toolbox for pharmaceutical research, particularly for the development of ⁶⁸Ga radiopharmaceuticals. Radiopharmaceutical toolbox: Polyazacycloalkanes with methylene(phosphinic acid) N-substituents such as functionalized triazacyclononane triphosphinates (shown), are very useful bifunctional chelators for radiopharmaceuticals, such as gallium-68-labeled peptide conjugates or radiolanthanide-based therapeutics.