N-Alkyl Carbamoylimidazoles as Versatile Synthons for the Synthesis of Urea-Based PSMA Inhibitors

Abstract

We describe N-alkyl carbamoylimidazoles as readily available and highly versatile synthons for synthesizing urea-based prostate-specific membrane antigen (PSMA) inhibitors. Urea formation proceeded in high yields (>80%) at room temperature under aqueous conditions. All novel compounds were tested for their PSMA inhibitory potency in a cell-based radiometric binding assay. Compound 17 was identified as a novel high-affinity PSMA inhibitor (IC₅₀ = 0.013 μM) suitable for developing an ¹⁸F-labeled radioligand for PET imaging of PSMA in prostate cancer.

Figure 1

Examples of clinically used KuE radioligands for the imaging and therapy of prostate cancer.

Scheme 1. Preparation of N-Alkyl Carbamoylimidazoles as Phosgene Substitutes and Isocyanate Equivalents for the Synthesis of Ureas (I), Carbamates (II), and Thiocarbamates (III)

Figure 2

Synthesis of PSMA ligands derived from 2-aminoadipic acid (R-NH₂ = 4-fluorobenzylamine; 6-fluoropyridine-3-amine).

Figure 3

Synthesis of KuATDA PSMA inhibitors 11a and 11b.

Figure 4

One-pot synthesis of KuE PSMA inhibitors.

Scheme 2. Proposed Replacement of ⁶⁸Ga HBED-CC Chelator (Blue) with a 4-Fluorobenzylidene-aminooxy-acetyl motif (red)

Figure 5

Synthesis of PSMA inhibitor 17.

Figure 6

Molecular docking results for compound 17 in the PSMA binding site. A) Molecular orientation of compound 17 (carbons are displayed as orange spheres) in the PSMA tunnel. B) Close-up view to highlight the molecular interactions observed between compound 17 and key active-site amino acid residues. For clarity, selected active-site residues (gray lines) and zinc ions (gray spheres) are displayed. The H-bonding interactions are indicated by dashed red lines.