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

Appl Radiat Isot. 2002 Mar;56(3):511-7. doi: 10.1016/s0969-8043(01)00155-5.

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.

MeSH terms

  • Alkylating Agents / pharmacology
  • Animals
  • DNA Repair
  • Drug Resistance
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Fluorine Radioisotopes
  • HeLa Cells
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / enzymology*
  • Neoplasms, Experimental / metabolism
  • O(6)-Methylguanine-DNA Methyltransferase / antagonists & inhibitors
  • O(6)-Methylguanine-DNA Methyltransferase / metabolism*
  • Purines / chemical synthesis
  • Purines / pharmacokinetics*
  • Purines / pharmacology
  • Tissue Distribution

Substances

  • 6-benzyloxy-7-(2-fluoroethyl)-7H-purine-2-yl-amine
  • 6-benzyloxy-9-(2-fluoroethyl)-9H-purin-2-yl-amine
  • Alkylating Agents
  • Enzyme Inhibitors
  • Fluorine Radioisotopes
  • Purines
  • O(6)-Methylguanine-DNA Methyltransferase