title: An approach to the evaluation of the activity of the DNA repair enzyme O6-methylguanine-DNA-methyl-transferase in tumor tissue in vivo: syntheses of 6-benzyloxy-9-(2-[18F]fluoroethyl)-9H-purin-2-yl-amine and 6-benzyloxy-7-(2-[18F]fluoroethyl)-7H-purin-2-yl-amine.
abstract: The resistance of tumor cells to the cytostatic activity of methylating and chloroethylating anticancer drugs is determined by the level of expression of the DNA repair protein O6-methylguanine-DNA-methyl-transferase (MGMT). The synthesis of labelled 6-benzyloxy-9H-purin-2-ylamine derivatives should hence allow a quantification of the MGMT status of tumor and non-target tissue in vivo. 6-benzyloxy-9-(2-fluoroethyl)-9H-purin-2-yl-amine and 6-benzyloxy-7-(2-fluoroethyl)-7H-purin-2-yl-amine were synthesized and evaluated in vitro, both showing an affinity of 1.8 microM. 6-benzyloxy-9-(2-[18F]fluoroethyl)-9H-purin-2-yl-amine and 6-benzyloxy-7-(2-[18F]fluoroethyl)-7H-purin-2-yl-amine were synthesized by alkylation of 6-benzyloxy-9H-purin-2-ylamine with 1-[18F]fluoro-2-tosylethane in optimized yields of 41% and 20%, respectively. Biodistribution studies were performed in nude mice, carrying mex+ (MGMT expressing) and mex- tumors.
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg-Universitat Mainz, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schirrmacher
authors.forename: Esther
authors.initials: E
authors.lastname: Nesseler
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Hamkens
authors.forename: Uta
authors.initials: U
authors.lastname: Eichhorn
authors.forename: Mathias
authors.initials: M
authors.lastname: Schreckenberger
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
authors.forename: Frank
authors.initials: F
authors.lastname: Rösch
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D004260:DNA Repair; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005462:Fluorine Radioisotopes; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011687:Purines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: C455285:6-benzyloxy-7-(2-fluoroethyl)-7H-purine-2-yl-amine; C455284:6-benzyloxy-9-(2-fluoroethyl)-9H-purin-2-yl-amine; D000477:Alkylating Agents; D004791:Enzyme Inhibitors; D005462:Fluorine Radioisotopes; D011687:Purines; D019853:O(6)-Methylguanine-DNA Methyltransferase