6533b871fe1ef96bd12d11fd

RESEARCH PRODUCT

Synthesis of 131I-labeled glucose-conjugated inhibitors of O6-methylguanine-DNA methyltransferase (MGMT) and comparison with nonconjugated inhibitors as potential tools for in vivo MGMT imaging.

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O 6 -Substituted guanine derivatives are powerful agents used for tumor cell sensitization by inhibition of the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT). To provide targeted accumulation of MGMT inhibitors in tumor tissue as well as tools for in vivo imaging, we synthesized iodinated C 8 -alkyl-linked glucose conjugates of 2-amino-6-(5-iodothenyl)-9H-purine (O 6 -(5-iodothenyl) guanine, ITG) and 2-amino-6-(3-iodobenzyloxy)-9H-purine (O 6 -(5-iodobenzyl) guanine, IBG). These compounds have MGMT inhibitor constants (IC 5 0 values) of 0.8 and 0.45 μM for ITGG and IBGG, respectively, as determined in HeLa S3 cells after 2-h incubation with inhibitor. To substantiate that the 1 3 1 I-(hetero)arylmethylene group at the O 6 -position of guanine is transferred to MGMT, both the glucose conjugated inhibitors ITGG and IBGG and the corresponding nonglucose conjugated compounds ITG and IBG were labeled with iodine-131. The radioiodinations of all compounds with [ 1 3 1 I]I - were performed with radiochemical yields of >70% for the destannylation of the corresponding tri-n-butylstannylated precursors. The binding ability of [ 1 3 1 I]-ITGG, [ 1 3 1 ]IBGG, [ 1 3 1 I]ITG, and [ 1 3 1 I]IBG to purified MGMT was tested. All radioactive compounds were substrates for MGMT, as demonstrated using a competitive repair assay. The newly synthesized radioactive inhibitors were utilized to study ex vivo biodistribution in mice, and the tumor-to-blood ratio of tissue uptake of [ 1 3 1 I]IBG and [ 1 3 1 I]IBGG was determined to be 0.24 and 0.76 after 0.5 h, respectively.