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.

In psychiatric disorders such as anxiety, depression and schizophrenia, 5-HT 2A receptors play an important role. In order to investigate them in vivo there is an increasing interest in selective and high-affinity radioligands for receptor binding studies using positron emission tomography (PET). Since available radioligands have disadvantages, R91150, which is a selective and high-affinity ligand for 5-HT 2A receptors, was labelled with fluorine-18. This was accomplished in six steps via 4-[18 F]fluorophenol and 1-(3-bromopropoxy)-4-[ 18 F]fluorobenzene within 190 min starting from no-carrier-added [ 18 F]fluoride. The overall radiochemical yield was 3.872% and the specific activity was at least 335 GBq/mmol at the end of the synthesis. First ex vivo studies in mice proved the uptake of [18 F]R91150 in the brain. Radiometabolite studies revealed no radiometabolites in the brain, whereas in the plasma at least two could be detected 30 min p.i. Further preclinical studies are encouraged to evaluate the potential of this new 5-HT 2A ligand as a radiotracer for PET.

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.

aIn some psychiatric disorders 5-HT 2A 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 [ 11 C]MDL 100907 for PET imaging of 5-HT 2A receptors and the more suitable half-life of fluorine-18, MDL 100907 was radiofluorinated in four steps using 1-(2-bromoethyl)-4-[18 F]fluorobenzene as a secondary labelling precursor. The complex reaction required an overall reaction time of 140 min and (7)-[18 F]MDL 100907 was obtained with a specific activity of at least 30 GBq/mmol (EOS) and an overall radiochemical yield of 1-2%. In order to verify its binding to 5-HT 2A receptors, in vitro rat brain autoradiography was conducted showing the typical distribution of 5-HT 2A receptors and a very low non-specific binding of about 6% in frontal cortex, using ketanserin or spiperone for blocking. Thus, [18 F]MDL 100907 appears to be a promising new 5-HT 2A PET ligand.

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