A Series of Halogenated Heterodimeric Inhibitors of Prostate Specific Membrane Antigen (PSMA) as Radiolabeled Probes for Targeting Prostate Cancer

Abstract

Prostate specific membrane antigen (PSMA) is a validated molecular marker for prostate cancer. A series of glutamate-urea (Glu-urea-X) heterodimeric inhibitors of PSMA were designed and synthesized where X = epsilon-N-(o-I, m-I, p-I, p-Br, o-Cl, m-Cl, p-Cl, p-F, H)-benzyl-Lys and epsilon-(p-I, p-Br, p-Cl, p-F, H)-phenylureido-Lys. The affinities for PSMA were determined by screening in a competitive binding assay. PSMA binding of the benzyllysine series was significantly affected by the nature of the halogen substituent (IC(50) values, Cl < I = Br << F = H) and the ring position of the halogen atom (IC(50) values, p-I < o-I << m-I). The halogen atom had little affect on the binding affinity in the para substituted phenylureido-Lys series. Two lead iodine compounds were radiolabeled with (123)I and (131)I and demonstrated specific PSMA binding on human prostate cancer cells, warranting evaluation as radioligands for the detection, staging, and monitoring of prostate cancer.

The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET/CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions

“…During the last 2 decades, many efforts have been undertaken to develop PSMA ligands (8)(9)(10)(11)(12)(13)(14)(15)(16). One of these ligands, the smallmolecule Glu-NH-CO-NH-Lys-(Ahx)-[ 68 Ga(HBED-CC)], also known as PSMA-11, PSMA HBED , Glu-CO-Lys(Ahx)-HBED-CC, DKFZ-PSMA-11, PSMA-HBED-CC, PSMA-HBED, PSMA, or Prostamedix, developed at the German Cancer Research Center Heidelberg (DKFZ), has become the most clinically used radiotracer.…”

Synthesis and positron emission tomography evaluation of 18F-Glu-Urea-Lys, a prostate-specific membrane antigen-based imaging agent for prostate cancer

“…Maresca et al (16) designed and synthesized a type of Glu-Urea-R compound which could be marked by 123I and 131I. This R-group and the substrate coupling with it may notably affect the affinity of the compounds to PSMA.…”

Preparation and affinity identification of glutamic acid-urea small molecule analogs in prostate cancer

“…Compared with the PSMA monoclonal antibody, Glu-urea-R is characterized by stable biological activity, short in vivo half-life, good permeability to tumor parenchyma and tumor metastases and low side-effects in vivo (8). At present, studies have demonstrated that Glu-urea-R PET/CT molecular probes may provide novel means for the diagnosis of Pca (12).…”

“…Compared with PSMA monoclonal antibodies, Glu-urea-R has the following advantages: Stable biological activity; short half-life in vivo; good permeability to tumor parenchyma and tumor metastases; and low side-effects in vivo (7,8 (12) designed and synthesized a number of Glu-urea-R molecules that may easily be labeled with radionuclide 123 iodine and 131 iodine. Those authors hypothesized that the chemical properties of the R-group and its coupling substrates may significantly impact the affinity of the Glu-urea-R to PSMA.…”