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

Abstract

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.

Lu-177-Labeled Hetero-Bivalent Agents Targeting PSMA and Bone Metastases for Radionuclide Therapy

“…Solid-phase extraction cartridges (SEP Pak Light QMA, Oasis HLB 3 cc) were obtained from Waters (Milford, MA, USA). The standard compound PSMA-617, 3 , 4 , and 12 were prepared according to the published literature. , All compounds tested are >95% pure by HPLC analysis (see Supporting Information).…”

“…The molar activities were in the range of 1.8−4.8 GBq/μmol similar to that reported previously using the similar DOTA-related chelates, DOTAGA and DOTA(GA) 2 . 43,44 Similarly, using a method reported previously, 43 68 GaCl 3 (0.5 mL, 55.5 MBq) in 0.05 M HCl of a 68 Ge/ 68 Ga generator and 50 μL of 0.5 N NaOAc were mixed and added to 20 μg of PSMA-617 or P17-079 (1) (in DMSO). The reaction mixture was incubated at 80 °C for 10 Adsorption Experiments on Hydroxyapatite.…”

“…The standard compound PSMA-617, 3, 4, and 12 were prepared according to the published literature. 44,56 All compounds tested are >95% pure by HPLC analysis (see Supporting Information).…”

“…30 Recently, a new PSMA-targeting imaging agent, [ 68 Ga]Ga-P16-093, with a novel Glu-NH-CO-NH-Lys-Phe-O-carboxymethyl)-Tyr-HBED-CC group (Figure 1) was successfully evaluated in humans. 37,39,41,45,46 By modifying the chelating group for Lu(III) chelation while maintaining the same PSMA binding moiety and linker (X = Glu-NH-CO-NH-Lys-Phe-Ocarboxymethyl)-Tyr-) of this diagnostic imaging agent, [ 68 Ga]Ga-P16-093 was successfully transformed to the radionuclide therapy agents, [ 177 Lu]Lu-P17−087, [ 177 Lu]Lu-P17-088 44 (Approach #1) and [ 177 Lu]Lu-P19-065 43 (Approach #2) (see Figure 2). To develop hetero-bivalent agents, an additional group, R = Gly-bisphosphonate, was strategically added for targeting both PSMA tumors and bone metastasis, resulting in the formation of two new hetero-bivalent targeting agents: [ 177 Lu]Lu-1 and [ 177 Lu]Lu-2 (Figures 1 and 2).…”

Synthesis, Preclinical Evaluation, and First-in-Human PET Study of [68Ga]-Labeled Biphenyl-Containing PSMA Tracers

“…To address the challenges associated with PSMA radioligands, researchers have proposed multiple chemical optimization strategies. These approaches involve modifying the linker between the targeting moiety and the pharmacophore to enhance binding affinity. − Additionally, incorporating albumin-binding moieties such as iodobenzylbutyric acid, ibuprofen, and Evans blue has been explored to extend the drug’s serum half-life. − Furthermore, investigating new isotopes for diagnostic and therapeutic purposes, such as 64 Cu, 89 Zr, and 111 In for imaging as well as 90 Y, 225 Ac, and 212 Pb for therapy, offers promising avenues for improvement. Increasing the number of pharmacophores is another effective strategy that has been shown to significantly enhance compound affinity.…”