68Ga-THP-PSMA: A PET Imaging Agent for Prostate Cancer Offering Rapid, Room-Temperature, 1-Step Kit-Based Radiolabeling

The clinical impact and accessibility of Ga-68 tracers for the prostatespecific membrane antigen (PSMA) and other targets would be greatly enhanced by the availability of a simple, 1-step kit-based labeling process. Radiopharmacy staff are accustomed to such procedures in the daily preparation of 99mTc radiopharmaceuticals. Currently, chelating agents used in Ga-68 radiopharmaceuticals do not meet this ideal. The aim of this study was to develop and evaluate preclinically a Ga-68 radiotracer for imaging PSMA expression that could be radiolabeled simply by addition of Ga-68 generator eluate to a cold kit. Methods: A conjugate of a tris(hydroxypyridinone) (THP) chelator with the established urea-based PSMA inhibitor was synthesized and radiolabeled with Ga-68 by adding generator eluate directly to a vial containing the cold precursors THP-PSMA and sodium bicarbonate, with no further manipulation. It was analyzed after 5 min by instant thin-layer chromatography and high-performance liquid chromatography. The product was subjected to in vitro studies to determine PSMA affinity using PSMA-expressing DU145-PSMA cells, with their nonexpressing analog DU145 as a control. In vivo PET imaging and ex vivo biodistribution studies were performed in mice bearing xenografts of the same cell lines, comparing Ga-68-THP-PSMA with Ga-68-HBEDCC- PSMA. Results: Radiolabeling was complete (>= 95%) within 5 min at room temperature, showing a single radioactive species by high-performance liquid chromatography that was stable in human serum for more than 6 h and showed specific binding to PSMAexpressing cells (concentration giving 50% inhibition of 361 6 60 nM). In vivo PET imaging showed specific uptake in PSMA-expressing tumors, reaching 5.6 6 1.2 percentage injected dose per cubic centimeter at 40-60 min and rapid clearance from blood to kidney and bladder. The tumor uptake, biodistribution, and pharmacokinetics were not significantly different from those of Ga-68-HBED-CC-PSMA except for reduced uptake in the spleen. Conclusion: Ga-68-THPPSMA has equivalent imaging properties but greatly simplified radiolabeling compared with other Ga-68-PSMA conjugates. THP offers the prospect of rapid, simple, 1-step, room-temperature syringe-and-vial radiolabeling of Ga-68 radiopharmaceuticals.