New PSMA-Targeting Ligands: Transformation from Diagnosis (Ga-68) to Radionuclide Therapy (Lu-177)

Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis and radionuclide therapy of prostate cancer. This study reports conversion of a previously reported Ga-imaging agent, [Ga]Ga-P16-093, to a Lu-177 radionuclide therapeutic agent. Substitution of the HBED-CC metal chelating group with DOTA(GA) led to P17-087 () and P17-088 (). Both agents showed excellent PSMA binding affinity (IC = 10-30 nM) comparable to that of recently FDA-approved [Lu]Lu-PSMA-617 (Pluvicto). Biodistribution studies in PSMA expressing tumor bearing mice showed that [Lu]Lu- exhibited very high tumor uptake and a fast blood clearance similar to those of [Lu]Lu-PSMA-617. Conversely, [Lu]Lu-, containing an albumin binder, extended its blood half-life and exhibited significantly higher uptake and longer tumor residence time than [Lu]Lu- and [Lu]Lu-PSMA-617. The switch from chelator HBED-CC to DOTA(GA) and the switch from the imaging isotope gallium-68 to the therapeutic isotope lutetium-177 have successfully transformed a PSMA-targeting agent from diagnosis to promising radionuclide therapeutic agents.