(68)Ga-THP-PSMA: a PET imaging agent for prostate cancer offering rapid, room temperature, one-step kit-based radiolabeling

The clinical impact and accessibility of (68)Ga tracers for the prostate-specific membrane antigen (PSMA) and other targets would be greatly enhanced by the availability of a simple, one-step kit-based labeling process. Radiopharmacy staff are accustomed to such procedures in the daily preparation of (99m)Tc radiopharmaceuticals. Currently, chelating agents used in (68)Ga radiopharmaceuticals do not meet this ideal.

To develop and evaluate preclinically a (68)Ga radiotracer for imaging PSMA expression that could be radiolabeled simply by addition of (68)Ga 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 (68)Ga 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 HPLC. The product was subjected to in vitro cell-binding studies to determine PSMA affinity using PSMA-expressing DU145-PSMA cells, with their non-expressing analog DU145 as a control. In vivo PET imaging and ex vivo biodistribution studies were carried out in mice bearing xenografts of the same cell lines, with (68)Ga-HBED-CC-PSMA as a comparator. Results: Radiolabeling was complete (>95%) within 5 min at room temperature, showing a single radioactive species by HPLC that was stable in human serum for >6 hours and showed specific binding to PSMA-expressing cells with an IC50 of 361 ± 60 nM. In vivo PET imaging showed specific uptake in PSMA-expressing tumors, reaching 5.6 ± 1.2 % ID/cm(3) at 40-60 min and rapid clearance from blood to kidney and bladder. The tumor uptake, biodistribution and pharmacokinetics were not significantly different to those of (68)Ga-HBED-CC-PSMA except for reduced uptake in the spleen. Conclusion: Conjugation of THP to the PSMA pharmacophore produces a (68)Ga tracer with equivalent imaging properties but greatly simplified radiolabeling compared to other (68)Ga-PSMA conjugates. THP offers the prospect of rapid, simple, one-step, room temperature "syringe-and-vial" radiolabeling of (68)Ga radiopharmaceuticals.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2017 Apr 13 [Epub ahead of print]

Jennifer D Young, Vincenzo Abbate, Cinzia Imberti, Levente K Meszaros, Michelle T Ma, Samantha Y A Terry, Robert C Hider, Greg E Mullen, Philip J Blower

Division of Imaging Sciences and Biomedical Engineering, King's College London, United Kingdom., Institute of Pharmaceutical Science, King's College London, United Kingdom.