Discovery of a High-Affinity Fluoromethyl Analog of [ 11 C]5-Cyano- N -(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([ 11 C]CPPC) and Their Comparison in Mouse and Monkey as Colony-Stimulating Factor 1 Receptor Positron Emission Tomography Radioligands.

Autor: Altomonte S; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health Building 10, B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, United States., Yan X; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health Building 10, B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, United States., Morse CL; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health Building 10, B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, United States., Liow JS; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health Building 10, B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, United States., Jenkins MD; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health Building 10, B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, United States., Montero Santamaria JA; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health Building 10, B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, United States., Zoghbi SS; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health Building 10, B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, United States., Innis RB; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health Building 10, B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, United States., Pike VW; Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health Building 10, B3 C346A, 10 Center Drive, Bethesda, Maryland 20892, United States.
Jazyk: angličtina
Zdroj: ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2023 Mar 10; Vol. 6 (4), pp. 614-632. Date of Electronic Publication: 2023 Mar 10 (Print Publication: 2023).
DOI: 10.1021/acsptsci.3c00003
Abstrakt: [ 11 C] CPPC has been advocated as a radioligand for colony-stimulating factor 1 receptor (CSF1R) with the potential for imaging neuroinflammation in human subjects with positron emission tomography (PET). This study sought to prepare fluoro analogs of CPPC with higher affinity to provide the potential for labeling with longer-lived fluorine-18 ( t 1/2 = 109.8 min) and for delivery of higher CSF1R-specific PET signal in vivo . Seven fluorine-containing analogs of CPPC were prepared and four were found to have high inhibitory potency (IC 50 in low to sub-nM range) and selectivity at CSF1R comparable with CPPC itself. One of these, a 4-fluoromethyl analog ( Psa374 ), was investigated more deeply by labeling with carbon-11 ( t 1/2 = 20.4 min) for PET studies in mouse and monkey. [ 11 C] Psa374 showed high peak uptake in monkey brain but not in mouse brain. Pharmacological challenges revealed no CSF1R-specific binding in either species at baseline. [ 11 C] CPPC also failed to show specific binding at baseline. Moreover, both [ 11 C] Psa374 and [ 11 C] CPPC showed brain efflux transporter substrate behavior in both species in vivo , although Psa374 did not show liability toward human efflux transporters in vitro . Further development of [ 11 C] Psa374 in non-human primate models of neuroinflammation with demonstration of CSF1R-specific binding would be required to warrant the fluorine-18 labeling of Psa374 with a view to possible application in human subjects.
Competing Interests: The authors declare no competing financial interest.
(Not subject to U.S. Copyright. Published 2023 by American Chemical Society.)
Databáze: MEDLINE
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