title: New molecular markers for prostate tumor imaging: a study on 2-methylene substituted fatty acids as new AMACR inhibitors.
abstract: The development of prostate carcinoma is associated with alterations in fatty acid metabolism. α-Methylacyl-CoA racemase (AMACR) is a peroxisomal and mitochondrial enzyme that catalyses interconversion between the (S)/(R)-isomers of a range of α-methylacyl-CoA thioesters. AMACR is involved in the β-oxidation of the dietary branched-chain fatty acids and bile acid intermediates. It is highly expressed in prostate (more than 95 %), colon (92 %), and breast cancers (44 %) but not in the respective normal or hyperplastic tissues. Thus, targeting of AMACR could be a new strategy for molecular imaging and therapy of prostate and some other cancers. Unlabeled 2-methylenacyl-CoA thioesters (12 a-c) were designed as AMACR binding ligands. The thioesters were tested for their ability to inhibit the AMACR-mediated epimerization of (25R)-THC-CoA and were found to be strong AMACR inhibitors. Radioiodinated (E)-(131) I-13-iodo-2-methylentridec-12-enoic acid ((131) I-7 c) demonstrated preferential retention in AMACR-positive prostate tumor cells (LNCaP, LNCaP C4-2wt and DU145) compared with both AMACR-knockout LNCaP C4-2 AMACR-siRNA and benign BPH1 prostate cell lines. A significant protein-bound radioactive fraction with main bands at 47 (sum of molecular weights of AMACR plus 12 c), 70, and 75 kDa was detected in LNCaP C4-2 wt cells. In contrast, only negligible amounts of protein-bound radioactivity were found in LNCaP C4-2 AMACR-siRNA cells.
authors.affiliation: Klinik für Nuklearmedizin, Aachen University, RWTH, Pauwelsstr. 30, 52074 Aachen, Germany.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Morgenroth
authors.forename: Elizaveta A
authors.initials: EA
authors.lastname: Urusova
authors.forename: Cornelia
authors.initials: C
authors.lastname: Dinger
authors.forename: Ehab
authors.initials: E
authors.lastname: Al-Momani
authors.forename: Thomas
authors.initials: T
authors.lastname: Kull
authors.forename: Gerhard
authors.initials: G
authors.lastname: Glatting
authors.forename: Holm
authors.initials: H
authors.lastname: Frauendorf
authors.forename: Olaf
authors.initials: O
authors.lastname: Jahn
authors.forename: Felix M
authors.initials: FM
authors.lastname: Mottaghy
authors.forename: Sven N
authors.initials: SN
authors.lastname: Reske
authors.forename: Boris D
authors.initials: BD
authors.lastname: Zlatopolskiy
mesh_terms: D002277:Carcinoma / Q000175:diagnosis* / Q000201:enzymology; D045744:Cell Line, Tumor; D058948:Cell Tracking / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000201:enzymology; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D005227:Fatty Acids; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase