Toward the Discovery and Development of PSMA Targeted Inhibitors for Nuclear Medicine Applications

Abstract

Background: The rising incidence rate of prostate cancer (PCa) has promoted the development of new diagnostic and therapeutic radiopharmaceuticals during the last decades. Promising improvements have been achieved in clinical practice using prostate specific membrane antigen (PSMA) labeled agents, including specific antibodies and small molecular weight inhibitors. Focusing on molecular docking studies, this review aims to highlight the progress in the design of PSMA targeted agents for a potential use in nuclear medicine.

Results: Although the first development of radiopharmaceuticals able to specifically recognize PSMA was exclusively oriented to macromolecule protein structure such as radiolabeled monoclonal antibodies and derivatives, the isolation of the crystal structure of PSMA served as the trigger for the synthesis and the further evaluation of a variety of low molecular weight inhibitors. Among the nuclear imaging probes and radiotherapeutics that have been developed and tested till today, labeled Glutamate-ureido inhibitors are the most prevalent PSMA-targeting agents for nuclear medicine applications.

Conclusion: PSMA represents for researchers the most attractive target for the detection and treatment of patients affected by PCa using nuclear medicine modalities. [99mTc]MIP-1404 is considered the tracer of choice for SPECT imaging and [68Ga]PSMA-11 is the leading diagnostic for PET imaging by general consensus. [18F]DCFPyL and [18F]PSMA-1007 are clearly the emerging PET PSMA candidates for their great potential for a widespread commercial distribution. After paving the way with new imaging tools, academic and industrial R&Ds are now focusing on the development of PSMA inhibitors labeled with alpha or beta minus emitters for a theragnostic application.

Keywords: PET; PSMA; Prostate cancer; SPECT; imaging; molecular docking; radionuclide therapy..

Fig. (1)

Crystal structure of human GCPII homodimer. A, the surface rendering shows protease domain (green), apical domain (blue), helical domain (yellow) and the active-site zinc ions (red spheres). PSMA active-site is encircled. B, interactions of zinc ions (purple spheres) with water (red sphere) and residues lining the active site of PSMA. C, internal cavity of human GCPII: surface representation of the S1’ pocket (yellow), the active-site (green), the arginine patch (cyan) and the entrance lid (orange) (realized by UCSF Chimera, PDB code 1Z8L).

Fig. (2)

Chemical sturctures of the main classes of PSMA small-molecule ligands.

Fig. (3)

CTT54 (PDB code 4P4B) and CTT1057 (PDB code 4JYW) interactions with the main residues lining the internal cavity of human GCPII. Inhibitors are coloured in red; the S1’ pocket residues in yellow; the active site in green; the arginine patch in cyan and the entrance lid in orange. All the residues and the ligands are in stick representation. The figure shows the CTT1057 interactions with the ABS residues inside the entrance lid, responsible of the its enhanced PSMA affinity (realized by UCSF Chimera).

Fig. (4)

Hydrophobic accessory pocket of GCPII in complex with DCMC, DCIT, DCFBC and DCIBzL (realized by UCSF Chimera. PDB code 3D7G, 3D7F, 3D7D, 3D7H). Pocket residues (R463, R534, R536, D465, E457) are shown as spheres (cyan) and inhibitors are in stick representation (red). The figure shows the Arg-463 side chain switch from “down” to “up” position in DCFBC and DCIBzL structures, due to the presence of longer P1 spacer.

Fig. (5)

Chemical structures of PSMA-617 ligand and [¹⁸F]PSMA-1007.

Fig. (6)

Chemical structures of [¹²³I]MIP-1072 and [¹²³I]MIP-1095.

Fig. (7)

Chemical structures of [^99mTc]MIP-1404, [^99mTc]MIP-1428, [^99mTc]MIP-1405 and [^99mTc]MIP-1427.

Fig. (8)

Chemical structure of [⁶⁸Ga]PSMA-11.

Fig. (9)

Chemical structure of [⁶⁸Ga]PSMA-I&T.