Preparation and evaluation of carborane-derived inhibitors of prostate specific membrane antigen (PSMA).
A series of C-hydroxy carborane derivatives of (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)-pentanedioic acid were prepared as a new class of boron rich inhibitors of prostate specific membrane antigen (PSMA), which is overexpressed on prostate cancer tumours and metastases. Closo-, nido- and iodo-carborane conjugates were prepared and screened in vitro where the water soluble iodinated cluster had the highest affinity with an IC50 value (73.2 nM) that was comparable to a known PSMA inhibitor 2-(phosphonomethyl)-pentanedioic acid (PMPA, 63.9 nM). The radiolabeled analogue was prepared using (123)I and the biodistribution determined in a prostate cancer model derived from a PSMA positive cell line (LNCaP) at 1, 2, 4, 6 and 24 h post injection (n = 4 per time point). The results showed good initial tumour uptake of 4.17% at 1 h, which remained at that level only decreasing somewhat at 6 h (3.59%). At the latter time point tumour-to-blood and tumour-to-muscle ratios peaked at 3.47 at 25.52 respectively. There was significant off-target binding particularly in the liver and gall bladder and a surprising amount of deiodination in vivo. Notwithstanding, this work demonstrates that carboranes can be used to prepare potent ligands for PSMA creating the opportunity to develop a new class of BNCT agents for prostate cancer.
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main St. West, Hamilton, Ont., CanadaL8S 4M1. valliant@mcmaster.ca.
Mohamed E
ME
El-Zaria
Afaf R
AR
Genady
Nancy
N
Janzen
Christina I
CI
Petlura
Denis R
DR
Beckford Vera
John F
JF
Valliant
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001896:Boron Compounds / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D005704:Gallbladder / Q000378:metabolism; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000378:metabolism; D014018:Tissue Distribution
D000954:Antigens, Surface; D001896:Boron Compounds; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II