Resolution, In vitro and In vivo evaluation of fluorine-18-labeled isomers of 1-azabicyclo[2.2.2]oct-3-yl α-(1-fluoropent-5-yl)-α-hydroxy-α- phenylacetate (FQNPe) as new PET candidates for the imaging of muscarinic- cholinergic receptor

H. Luo, A. L. Beets, M. J. McAllister, M. Greenbaum, D. W. McPherson, F. F. Knapp

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Abstract

1-Azabicyclo[2.2.2]oct-3-yl α-(1-fluoropent-5-yl)-α-hydroxy-α- phenylacetate (FQNPe, 2), an analogue of 1-azabicyclo[2.2.2]oct-3-yl α,α- (diphenyl)-α-hydroxyacetate (QNB), was resolved into its four stereoisomers. In vitro binding assays of the stereoisomers of 2 demonstrated that while the (S,S)-isomer did not have significant receptor binding, the other stereoisomers of 2 bound with high affinity to the various mAChR subtypes [K(i), nM: ml, (R,R), 0.33; (R,S), 1.4; (S,R), 3.8; m2, (R,R), 0.1; (R,S), 4.2; (S,R), < 75% binding; m3, (R,R), 0.34; (R,S), 3.1; (S,R), 7.6]. The (R,R)- and (R,S)stereoisomers of 2 were radiolabeled with fluorine-18 via a two step procedure in radiochemical yields of 12-21% (n=2) and 9% (decayed corrected to beginning of synthesis), respectively. In vivo biodistribution studies demonstrated significant uptake of [18F]-(R,R)-2 in cerebral mAChR- rich regions of rat brains up to 3 h post injection. Low accumulation of fluorine-18 in the bone indicated that [18F]-(R,R)-2 displayed significant in vivo stability. In contrast. [18F]-(R,S)-2 demonstrated rapid washout from all cerebral regions. Preinjection of (R)-QNB (3 mg/kg) 1 h prior to the injection of [18F]-(R,R)-2 blocked the uptake of activity in cerebral regions by approximately 90% while the preinjection of haloperidol (3 mg/kg) 1 h prior to the injection of [18F]-(R,R)2 demonstrated no statistically significant effect on the binding of the radiotracer. An ex vivo metabolic study utilizing [18F]-(R,R)-2 demonstrated that greater than 96% of the organic soluble radioactivity which localized in the brain and heart at 1 h post-injection migrated on TLC with the same mobility as the parent. Although [18F]-(R,R)-2 did not demonstrate a desired in vitro or in vivo mAChR subtype selectivity, these results suggest that the introduction of a fluoroalkyl group in various benzylic analogues of QNB is an attractive radiolabeling moiety for further evaluation in the design of selective PET mAChR imaging ligands.

Original languageEnglish
Pages (from-to)681-704
Number of pages24
JournalJournal of Labelled Compounds and Radiopharmaceuticals
Volume41
Issue number8
DOIs
StatePublished - Aug 1998

Keywords

  • 3-quinuclidinyl esters
  • Fluorine-18
  • Muscarinic receptor

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