Journal
CHINESE CHEMICAL LETTERS
Volume 33, Issue 7, Pages 3543-3548Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cclet.2022.03.099
Keywords
sigma(1) receptor; Enantiomer; Rad iotracer; Positron emission tomography; Fluorine-18
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Funding
- Beijing Natural Science Foundation [7212203]
- National Natural Science Foundation of China [21876013]
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The study found that Racemic [F-18]FBFP is a potent sigma(1) receptor radiotracer with superior imaging properties. The two enantiomers showed comparable high affinity for sigma(1) receptors, with one behaving as an antagonist and the other as an agonist. In experimental tests on mice and rats, both enantiomers displayed good brain uptake and binding specificity.
Racemic [F-18]FBFP ([F-18]1) proved to be a potent sigma(1) receptor radiotracer with superior imaging properties. The pure enantiomers of unlabeled compounds (S)- and (R)-1 and the corresponding iodonium ylide precursors were synthesized and characterized. The two enantiomers (S)1 and (R)-1 exhibited comparable high affinity for sigma(1) receptors and selectivity over a 2 receptors. The Ca2+ fluorescence assay indicated that (R)-1 behaved as an antagonist and (S)-1 as an agonist for sigma(1) receptors. The F-18-labeled enantiomers (S)- and (R)-[F-18]1 were obtained in >99% enantiomeric purity from the corresponding enantiopure iodonium ylide precursors with radiochemical yield of 24.4% +/- 2.6% and molar activity of 86-214 GBq/mu mol. In ICR mice both (S)- and (R)-[F-18]1 displayed comparable high brain uptake, brain-to-blood ratio, in vivo stability and binding specificity in the brain and peripheral organs. In micro-positron emission tomography (PET) imaging studies in rats, (S)-[F-18]1 exhibited faster clearance from the brain than (R)-[F-18]1, indicating different brain kinetics of the two enantiomers. Both (S)- and (R)-[F-18]1 warrant further evaluation in primates to translate a single enantiomer with more suitable kinetics for imaging the sigma(1) receptors in humans. (C) 2022 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
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