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

Abstract Introduction 68 Ga is a positron-emitting nuclide that has significant imaging potential given that, unlike cyclotron-produced 18 F, the isotope can be produced on-site utilizing a 68 Ge/ 68 Ga generator. We recently synthesized a novel bone-seeking agent by coupling a bisphosphonate with the 68 Ga chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). This study presents a first report on the potential of this 68 Ga bone-seeking radiopharmaceutical in the detection of bone metastases. Methods 4-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). 68 Ga-labeled NOTA-BP ([ 68 Ga]NOTA-BP) was prepared by complexation of NOTA-BP with [ 68 Ga] gallium chloride and evaluated in in vitro experiments, biodistribution experiments and micro-positron emission tomography (PET) imaging experiments. Results The labeling of NOTA-BP with 68 Ga was completed by heating for 10 min. [ 68 Ga]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, [ 68 Ga]NOTA-BP demonstrated high bone uptake potential. Compared with 99m Tc-labeled methylene diphosphonate ([ 99m Tc]MDP) and [ 18 F]fluoride, [ 68 Ga]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 [ 68 Ga]NOTA-BP. Conclusion We have developed a novel 68 Ga-radiolabeled bone-seeking agent. This [ 68 Ga]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.