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Synthesis and Screening in Mice of Fluorine-Containing PET Radioligands for TSPO: Discovery of a Promising 18 F-Labeled Ligand

Authors
 Fabrice G Siméon  ;  Jae-Hoon Lee  ;  Cheryl L Morse  ;  Ian Stukes  ;  Sami S Zoghbi  ;  Lester S Manly  ;  Jeih-San Liow  ;  Robert L Gladding  ;  Rachel M Dick  ;  Xuefeng Yan  ;  Sabrina Taliani  ;  Barbara Costa  ;  Claudia Martini  ;  Federico Da Settimo  ;  Sabrina Castellano  ;  Robert B Innis  ;  Victor W Pike 
Citation
 JOURNAL OF MEDICINAL CHEMISTRY, Vol.64(22) : 16731-16745, 2021-11 
Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN
 0022-2623 
Issue Date
2021-11
MeSH
Animals ; Brain / diagnostic imaging ; Brain / metabolism ; Carbon Radioisotopes / chemistry ; Fluorine / analysis* ; Humans ; Ligands ; Mice ; Positron-Emission Tomography* ; Radiopharmaceuticals / administration & dosage* ; Radiopharmaceuticals / chemistry ; Receptors, GABA / metabolism*
Abstract
Translocator protein 18 kDa (TSPO) is a biomarker of neuroinflammation. [11C]ER176 robustly quantifies TSPO in the human brain with positron emission tomography (PET), irrespective of subject genotype. We aimed to develop an ER176 analog with potential for labeling with longer-lived fluorine-18 (t1/2 = 109.8 min). New fluoro and trifluoromethyl analogs of ER176 were prepared through a concise synthetic strategy. These ligands showed high TSPO affinity and low human genotype sensitivity. Each ligand was initially labeled by a generic 11C-methylation procedure, thereby enabling speedy screening in mice. Each radioligand was rapidly taken up and well retained in the mouse brain at baseline after intravenous injection. Preblocking of TSPO showed that high proportions of brain uptake were specifically bound to TSPO at baseline. Overall, the 3-fluoro analog of [11C]ER176 ([11C]3b) displayed the most promising imaging properties. Therefore, a method was developed to label 3b with [18F]fluoride ion. [18F]3b gave similarly promising PET imaging results and deserves evaluation in higher species.
Files in This Item:
T202124841.pdf Download
DOI
10.1021/acs.jmedchem.1c01562
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
Yonsei Authors
Lee, Jae Hoon(이재훈) ORCID logo https://orcid.org/0000-0002-9898-9886
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/187546
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