Radiosynthesis and evaluation of 4-(6-[18F]Fluoro-4-(5-isopropoxy-1H-indazol-3-yl)pyridin-2-yl)morpholine as a novel radiotracer candidate targeting leucine-rich repeat kinase 2
| Autor: | Masayuki Hanyu, Yiding Zhang, Nobuki Nengaki, Wakana Mori, Hong Zhang, Yasushi Hattori, Katsushi Kumata, Tomoteru Yamasaki, Masayuki Fujinaga, Ming-Rong Zhang |
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| Rok vydání: | 2020 |
| Předmět: |
Pharmacology
Biodistribution 010405 organic chemistry Stereochemistry Organic Chemistry Radiosynthesis Pharmaceutical Science 01 natural sciences Biochemistry LRRK2 0104 chemical sciences Chemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine chemistry In vivo Morpholine Drug Discovery Molecular Medicine Protecting group IC50 Lead compound 030217 neurology & neurosurgery |
| Zdroj: | RSC Med Chem |
| ISSN: | 2632-8682 |
| Popis: | Mutations that increase leucine-rich repeat kinase 2 (LRRK2) activity in the brain are associated with Parkinson's disease. Here, we synthesized a novel compound 4-(6-fluoro-4-(5-isopropoxy-1H-indazol-3-yl)pyridin-2-yl)morpholine (FIPM) and labeled it with fluorine-18 ((18)F), to develop a positron emission tomography (PET) tracer for in vivo visualization of LRRK2 in the brain. FIPM showed high in vitro binding affinity for LRRK2 (IC(50) = 8.0 nM). [(18)F]FIPM was prepared in 5% radiochemical yield (n = 5), by inserting (18)F into a pyridine ring, followed by removal of the protecting group. After HPLC separation and formulation, [(18)F]FIPM was acquired with >97% radiochemical purity and 103–300 GBq μmol(–1) of molar activity at the end of radiosynthesis. Biodistribution and small-animal PET studies in mice indicated a low in vivo specific binding of [(18)F]FIPM. While [(18)F]FIPM presented limited potential as an in vivo PET tracer for LRRK2, we suggested that it can be used as a lead compound for developing new radiotracers with improved in vivo brain properties. |
| Databáze: | OpenAIRE |
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