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

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 tra...

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Published in:Journal of medicinal chemistry 2015-02, Vol.58 (3), p.1513-1523
Main Authors: Fujinaga, Masayuki, Xie, Lin, Yamasaki, Tomoteru, Yui, Joji, Shimoda, Yoko, Hatori, Akiko, Kumata, Katsushi, Zhang, Yiding, Nengaki, Nobuki, Kawamura, Kazunori, Zhang, Ming-Rong
Format: Article
Language:English
Subjects:
Animals
Benzamides - chemical synthesis
Benzamides - chemistry
Dose-Response Relationship, Drug
Humans
Male
Melanoma - diagnosis
Melanoma - drug therapy
Melanoma - metabolism
Mice
Mice, Inbred C57BL
Molecular Imaging
Molecular Structure
Neoplasms, Experimental - diagnosis
Neoplasms, Experimental - drug therapy
Neoplasms, Experimental - metabolism
Receptors, Metabotropic Glutamate - analysis
Receptors, Metabotropic Glutamate - antagonists & inhibitors
Receptors, Metabotropic Glutamate - metabolism
Structure-Activity Relationship
Thiazoles - chemical synthesis
Thiazoles - chemistry
Tissue Distribution
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Summary: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 (K i, 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm501845n