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

Introduction: Ga-68 is a positron-emitting nuclide that has significant imaging potential given that, unlike cyclotron-produced F-18, the isotope can be produced on-site utilizing a Ge-68/Ga-68 generator. We recently synthesized a novel bone-seeking agent by coupling a bisphosphonate with the Ga-68 chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). This study presents a first report on the potential of this Ga-68 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-l-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). Ga-68-labeled NOTA-BP ([Ga-68]NOTA-BP) was prepared by complexation of NOTA-BP with [Ga-68] 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 Ga-68 was completed by heating for 10 min. [Ga-68]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, [Ga-68]NOTA-BP demonstrated high bone uptake potential. Compared with Tc-99m-labeled methylene diphosphonate ([Tc-99m]MDP) and [F-18] fluoride, [Ga-68]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 [Ga-68]NOTA-BP. Conclusion: We have developed a novel Ga-68-radiolabeled bone-seeking agent. This [Ga-68]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. (C) 2011 Elsevier Inc. All rights reserved.