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Start Over Author "Hamkens, W." Publisher pergamon press
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1. 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.

Author

Schirrmacher R, Nesseler E, Hamkens W, Eichhorn U, Schreckenberger M, Kaina B, and Rösch F

Subjects
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 metabolism, O(6)-Methylguanine-DNA Methyltransferase antagonists & inhibitors, Purines chemical synthesis, Purines pharmacology, Tissue Distribution, Neoplasms, Experimental enzymology, O(6)-Methylguanine-DNA Methyltransferase metabolism, Purines pharmacokinetics
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.

Published
2002
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