932738-80-2Relevant academic research and scientific papers
Derisking the Cu-Mediated 18F-Fluorination of Heterocyclic Positron Emission Tomography Radioligands
Taylor, Nicholas J.,Emer, Enrico,Preshlock, Sean,Schedler, Michael,Tredwell, Matthew,Verhoog, Stefan,Mercier, Joel,Genicot, Christophe,Gouverneur, Véronique
supporting information, p. 8267 - 8276 (2017/06/27)
Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.
Synthesis and evaluation of 4-halogeno- N -[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]- N -[11C]methylbenzamide for imaging of metabotropic glutamate 1 receptor in melanoma
Fujinaga, Masayuki,Xie, Lin,Yamasaki, Tomoteru,Yui, Joji,Shimoda, Yoko,Hatori, Akiko,Kumata, Katsushi,Zhang, Yiding,Nengaki, Nobuki,Kawamura, Kazunori,Zhang, Ming-Rong
, p. 1513 - 1523 (2015/03/04)
Metabotropic glutamate 1 (mGlu1) receptor is found not only in the brain but also in melanomas and breast cancers. mGlu1 is a promising target for molecular imaging-based diagnosis and treatment of melanoma because its overexpression induces melanocyte carcinogenesis. Here we developed three PET tracers: 4-halogeno-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol- 2-yl]-N-[11C]methylbenzamide ([11C]4-6), which exhibited high uptake in target tumor and decreased uptake in nontarget brain tissues. In vitro binding assay indicated high to moderate binding affinities of 4-6 (Ki, 22-143 nM) for mGlu1 receptor. In vivo biodistribution studies in mice implanted with B16F10 melanoma cells confirmed high radioactive uptake in tumor and low uptake in blood, skin, and muscles. Inhibition of mGlu1 receptor using an mGlu1-selective ligand led to reduced radioactive uptake in the tumor. [11C]6 displayed the highest ratio of uptake between tumor and nontarget tissue and may prove useful as a PET tracer for mGlu1 imaging in melanoma.
Synthesis and evaluation of novel radioligands for positron emission tomography imaging of metabotropic glutamate receptor subtype 1 (mGluR1) in rodent brain
Fujinaga, Masayuki,Yamasaki, Tomoteru,Yui, Joji,Hatori, Akiko,Xie, Lin,Kawamura, Kazunori,Asagawa, Chiharu,Kumata, Katsushi,Yoshida, Yuichiro,Ogawa, Masanao,Nengaki, Nobuki,Fukumura, Toshimitsu,Zhang, Ming-Rong
, p. 2342 - 2352 (2012/05/31)
We designed three novel positron emission tomography ligands, N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-[ 11C]methoxy-N-methylbenzamide ([11C]6), 4-[ 18F]fluoroethoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1, 3-thiazol-2-yl]-N-methylbenzamide ([18F]7), and 4-[ 18F]fluoropropoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1, 3-thiazol-2-yl]-N-methylbenzamide ([18F]8), for imaging metabotropic glutamate receptor type 1 (mGluR1) in rodent brain. Unlabeled compound 6 was synthesized by benzoylation of 4-pyrimidinyl-2-methylaminothiazole 10, followed by reaction with isopropylamine. Removal of the methyl group in 6 gave phenol precursor 12 for radiosynthesis. Two fluoroalkoxy analogues 7 and 8 were prepared by reacting 12 with tosylates 13 and 14. Radioligands [ 11C]6, [18F]7, and [18F]8 were synthesized by O-[11C]methylation or [18F]fluoroalkylation of 12. Compound 6 showed high in vitro binding affinity for mGluR1, whereas 7 and 8 had weak affinity. Autoradiography using rat brain sections showed that [ 11C]6 binding is aligned with the reported distribution of mGluR1 with high specific binding in the cerebellum and thalamus. PET study with [ 11C]6 in rats showed high brain uptake and a similar distribution pattern to that in autoradiography, indicating the usefulness of [ 11C]6 for imaging brain mGluR1.
Discovery and in vitro and in vivo profiles of 4-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide as novel class of an orally active metabotropic glutamate receptor 1 (mGluR1) antagonist
Satoh, Atsushi,Nagatomi, Yasushi,Hirata, Yukari,Ito, Satoru,Suzuki, Gentaroh,Kimura, Toshifumi,Maehara, Shunsuke,Hikichi, Hirohiko,Satow, Akio,Hata, Mikiko,Ohta, Hisashi,Kawamoto, Hiroshi
scheme or table, p. 5464 - 5468 (2010/06/19)
We identified 4-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide 27 as a potent mGluR1 antagonist. The compound possessed excellent subtype selectivity and good PK profile in rats. It also demonstrated relatively potent a
