title: 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.
abstract: 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(50) values) of 0.8 and 0.45 microM for ITGG and IBGG, respectively, as determined in HeLa S3 cells after 2-h incubation with inhibitor. To substantiate that the (131)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 [(131)I]I(-) were performed with radiochemical yields of >70% for the destannylation of the corresponding tri-n-butylstannylated precursors. The binding ability of [(131)I]ITGG, [(131)]IBGG, [(131)I]ITG, and [(131)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 [(131)I]IBG and [(131)I]IBGG was determined to be 0.24 and 0.76 after 0.5 h, respectively.
authors.affiliation: Institute of Nuclear Chemistry, University of Mainz, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Mühlhausen
authors.forename: Ralf
authors.initials: R
authors.lastname: Schirrmacher
authors.forename: Markus
authors.initials: M
authors.lastname: Piel
authors.forename: Bernd
authors.initials: B
authors.lastname: Lecher
authors.forename: Manuela
authors.initials: M
authors.lastname: Briegert
authors.forename: Andrea
authors.initials: A
authors.lastname: Piee-Staffa
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
authors.forename: Frank
authors.initials: F
authors.lastname: Rösch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005947:Glucose / Q000737:chemistry*; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007456:Iodine Isotopes; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013997:Time Factors; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007456:Iodine Isotopes; C507820:O(6)-(5-iodobenzyl)guanine; C507819:O(6)-(5-iodothenyl)guanine; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D005947:Glucose