Synthesis and evaluation of a novel 68Ga-chelate-conjugated bisphosphonate as a bone-seeking agent for PET imaging

Introduction68Ga is a positron-emitting nuclide that has significant imaging potential given that, unlike cyclotron-produced 18F, the isotope can be produced on-site utilizing a 68Ge/68Ga generator. We recently synthesized a novel bone-seeking agent by coupling a bisphosphonate with the 68Ga chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). This study presents a first report on the potential of this 68Ga bone-seeking radiopharmaceutical in the detection of bone metastases.Methods4-Amino-1-hydroxybutylidene-1,1-bisphosphonate was conjugated with 2-[4,7-di(carboxymethyl)-1,4,7-triazonan-1-yl]pentanedioic acid, yielding 2-[4,7-di(carboxymethyl)-1,4,7-triazonan-1-yl]-5-[(4-hydroxy-4,4-diphosphonobutyl)amino]-5-oxopentanoic acid (NOTA-BP). 68Ga-labeled NOTA-BP ([68Ga]NOTA-BP) was prepared by complexation of NOTA-BP with [68Ga] gallium chloride and evaluated in in vitro experiments, biodistribution experiments and micro-positron emission tomography (PET) imaging experiments.ResultsThe labeling of NOTA-BP with 68Ga was completed by heating for 10 min. [68Ga]NOTA-BP was determined to have a radiochemical purity of over 95%, a high affinity for hydroxyapatite and a high stability in plasma. In in vivo biodistribution experiments, [68Ga]NOTA-BP demonstrated high bone uptake potential. Compared with 99mTc-labeled methylene diphosphonate ([99mTc]MDP) and [18F]fluoride, [68Ga]NOTA-BP exhibited faster blood clearance and a higher bone-to-blood ratio. In addition, mouse model bone metastasis was detected by micro-PET imaging at 1 h postinjection of [68Ga]NOTA-BP.ConclusionWe have developed a novel 68Ga-radiolabeled bone-seeking agent. This [68Ga]NOTA-BP complex was found to have a high bone affinity and rapid blood clearance, and may thus prove to be useful as a bone-seeking agent for clinical PET.