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 ⁶⁸Ga-imaging agent, [⁶⁸Ga]Ga-P16-093, to a Lu-177 radionuclide therapeutic agent. Substitution of the HBED-CC metal chelating group with DOTA(GA)₂ led to P17-087 (4) and P17-088 (7). Both agents showed excellent PSMA binding affinity (IC₅₀ = 10-30 nM) comparable to that of recently FDA-approved [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto). Biodistribution studies in PSMA expressing tumor bearing mice showed that [¹⁷⁷Lu]Lu-4 exhibited very high tumor uptake and a fast blood clearance similar to those of [¹⁷⁷Lu]Lu-PSMA-617. Conversely, [¹⁷⁷Lu]Lu-7, containing an albumin binder, extended its blood half-life and exhibited significantly higher uptake and longer tumor residence time than [¹⁷⁷Lu]Lu-4 and [¹⁷⁷Lu]Lu-PSMA-617. The switch from chelator HBED-CC to DOTA(GA)₂ 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.