0000000000230161
AUTHOR
Ute Mühlhausen
Synthesis of 2-amino-6-(2-[18F]fluoro-pyridine-4-ylmethoxy)-9-(octyl-β-d-glucosyl)-purine: a novel radioligand for positron emission tomography studies of the O6-methylguanine-DNA methyltransferase (MGMT) status of tumour tissue
Abstract The synthesis of the novel glucose conjugated O6-methylguanine-DNA methyltransferase (MGMT) inhibitor 2-amino-6-(2-[18F]fluoro-pyridine-4-ylmethoxy)-9-(octyl-α- d -glucosyl)-purine is reported. This compound might serve as a radiotracer for the determination of the MGMT status of tumour tissue.
Inhibition of O6-Methylguanine-DNA Methyltransferase by Glucose-Conjugated Inhibitors: Comparison with Nonconjugated Inhibitors and Effect on Fotemustine and Temozolomide-Induced Cell Death
The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is an important suicide enzyme involved in the defense against O(6)-alkylating mutagens. It also plays a role in the resistance of tumors to anticancer drugs targeting the O(6)-position of guanine, such as temozolomide and fotemustine. Several potent MGMT inhibitors have been developed sensitizing cells to O(6)-alkylating agents. Aimed at targeting MGMT inhibitors to tumor cells, we synthesized MGMT inhibitory compounds conjugated with glucose to improve uptake in tumor cells. Here, we compared O(6)-benzylguanine, O(6)-2-fluoropyridinylmethylguanine (O(6)FPG), O(6)-3-iodobenzylguanine, O(6)-4-bromothenylguanine, and O(6)…
Synthesis, radiofluorination and first evaluation of (±)-[18F]MDL 100907 as serotonin 5-HT2Areceptor antagonist for PET
In some psychiatric disorders 5-HT2A receptors play an important role. In order to investigate those in vivo there is an increasing interest in obtaining a metabolically stable, subtype selective and high affinity radioligand for receptor binding studies using positron emission tomography (PET). Combining the excellent in vivo properties of [11C]MDL 100907 for PET imaging of 5-HT2A receptors and the more suitable half-life of fluorine-18, MDL 100907 was radiofluorinated in four steps using 1-(2-bromoethyl)-4-[18F]fluorobenzene as a secondary labelling precursor. The complex reaction required an overall reaction time of 140 min and (±)-[18F]MDL 100907 was obtained with a specific activity of…
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.
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 tha…