New molecular markers for prostate tumor imaging: a study on 2-methylene substituted fatty acids as new AMACR inhibitors

A. Morgenroth, E.A. Urusova, C. Dinger, E. Al Momani, T. Kull, G. Glatting, H. Frauendorf, O. Jahn, F.M. Mottaghy, S.N. Reske, B.D. Zlatopolskiy

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The development of prostate carcinoma is associated with alterations in fatty acid metabolism. alpha-Methylacyl-CoA racemase (AMACR) is a peroxisomal and mitochondrial enzyme that catalyses interconversion between the (S)/(R)-isomers of a range of alpha-methylacyl-CoA thioesters. AMACR is involved in the beta-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.
Original languageEnglish
Pages (from-to)10144-10150
Number of pages7
JournalChemistry: a European journal
Volume17
Issue number36
DOIs
Publication statusPublished - Aug 2011

Keywords

  • antitumor agents
  • fatty acids
  • imaging agents
  • inhibitors
  • metabolism
  • radiopharmaceuticals
  • METHYLACYL-COA-RACEMASE
  • C-11-CHOLINE PET/CT
  • CANCER
  • EXPRESSION
  • ADENOCARCINOMA
  • CARCINOMA
  • DESIGN
  • ENZYME
  • ESTERS
  • GENE

Cite this

Morgenroth, A., Urusova, E. A., Dinger, C., Al Momani, E., Kull, T., Glatting, G., Frauendorf, H., Jahn, O., Mottaghy, F. M., Reske, S. N., & Zlatopolskiy, B. D. (2011). New molecular markers for prostate tumor imaging: a study on 2-methylene substituted fatty acids as new AMACR inhibitors. Chemistry: a European journal, 17(36), 10144-10150. https://doi.org/10.1002/chem.201003176