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.