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Resolution, in vitro and in vivo evaluation of fluorine‐18‐labeled isomers of 1‐azabicyclo[2.2.2]oct‐3‐ylα‐(1‐fluoropent‐5‐yl)α‐hydroxy‐α‐phenylacetate (FQNPe) as new PET candidates for the imaging of muscarinic‐cholinergic receptor
Author(s) -
Luo H.,
Beets A. L.,
McAllister M. J.,
Greenbaum M.,
McPherson D. W.,
Knapp F. F.
Publication year - 1998
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/(sici)1099-1344(1998080)41:8<681::aid-jlcr131>3.0.co;2-q
Subject(s) - chemistry , in vivo , stereochemistry , biodistribution , enantiomer , in vitro , bicyclic molecule , radiosynthesis , phenylacetate , biochemistry , microbiology and biotechnology , biology
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‐ylα, 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: m1 , (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 [ 18 F]‐(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 [ 18 F]‐(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 [ 18 F]‐(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 [ 18 F]‐(R,R)‐2 demonstrated no statistically significant effect on the binding of the reactor. An ex vivo metabolic study utilizing [ 18 F]‐(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 [ 18 F]‐(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 furthering evaluation in the design of selective PET mAChR imaging ligands.