期刊
ACS CHEMICAL NEUROSCIENCE
卷 9, 期 11, 页码 2610-2619出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.8b00102
关键词
COX-1; PET; radioligand; brain; carbon-11; fluorine-18
资金
- Intramural Research Program of the National Institutes of Health (NIH)
- NIMH [ZIA-MH002793, ZIA-MH002795]
- NATIONAL INSTITUTE OF MENTAL HEALTH [ZIAMH002793, ZIAMH002795] Funding Source: NIH RePORTER
Cyclooxygenase-1 (COX-1) is a key enzyme in the biosynthesis of proinflammatory thromboxanes and prostaglandins and is found in glial and neuronal cells within brain. COX-1 expression is implicated in numerous neuroinflammatory states. We aim to find a direct-acting positron emission tomography (PET) radioligand for imaging COX-1 in human brain as a potential biomarker of neuroinflammation and for serving as a tool in drug development. Seventeen 3-substituted 1,5-diaryl-1H-1,2,4-triazoles were prepared as prospective COX-1 PET radioligands. From this set, three 1,5-(4-methoxypheny1)-1H-1,2,4-triazoles, carrying a 3-methoxy (5), 3-(1,1,1-trifluoroethoxy) (20), or 3-fluoromethoxy substituent (6), were selected for radioligand development, based mainly on their high affinities and selectivities for inhibiting human COX-1, absence of carboxyl group, moderate computed lipophilicities, and scope for radiolabeling with carbon-11 (t(1/2) = 20.4 min) or fluorine-18 (t(1/2) = 109.8 min). Methods were developed for producing [C-11]5, [C-11]20, and [d(2)-F-18]6 from hydroxy precursors in a form ready for intravenous injection for prospective evaluation in monkey with PET.
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