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

• Published in: Journal of labelled compounds & radiopharmaceuticals Vol. 41; no. 8; pp. 681 - 704
• Main Authors: Luo, H., Beets, A. L., McAllister, M. J., Greenbaum, M., McPherson, D. W., Knapp, F. F.
• Format: Journal Article
• Language: English
• Published: Chichester John Wiley & Sons, Ltd 01.08.1998; Wiley
• Subjects: 3-quinuclidinyl esters; Aliphatic compounds; Biochemical Research Methods; Biochemistry & Molecular Biology; Biological and medical sciences; Chemistry; Chemistry, Analytical; Chemistry, Medicinal; Cholinergic system; Exact sciences and technology; fluorine-18; Life Sciences & Biomedicine; Medical sciences; muscarinic receptor; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Organic chemistry; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Preparations and properties; Science & Technology; HUMAN BRAIN; ACETYLCHOLINE; SUBTYPES; HALOPERIDOL; ALZHEIMERS-DISEASE; HIGH-AFFINITY; ALPHA-HYDROXY-ALPHA-(1-IODO-1-PROPEN-3-YL)-ALPHA-PHENYLACETATE; 3-quinuclidinyl esters; muscarinic receptor; fluorine-18; 3-QUINUCLIDINYL BENZILATE; BINDING; OPTICAL ISOMERS; Intravenous administration; Fluorine 18; Hydroxyester; Quinuclidine derivatives; Rat; Nitrogen heterocycle; Ligand; Tissue; Cholinergic receptor; Scintigraphic agent; Enantiomer; Bicyclic compound; Female; Chemical synthesis; Human; Fluorine Isotopes; Radiolabelling; Rodentia; In vitro; Biological activity; In vivo; Vertebrata; Biological fixation; Mammalia; Optical resolution; Animal; Distribution; Affinity; Muscarinic receptor; Pharmacokinetics; Diastereomer
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/(SICI)1099-1344(1998080)41:8<681::AID-JLCR131>3.0.CO;2-Q

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 [Ki, 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 [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 reactor. 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 furthering evaluation in the design of selective PET mAChR imaging ligands.