Structure Elucidation Via Stereoselective Synthesis of the Acetate Center of 1-Azabicyclo[2.2.2]oct-3-yl α-Hydroxy- α-(1-iodo-1-propen-3-yl)-α-phenylacetate (IQNP). A High Affinity Muscarinic Imaging Agent for SPECT

McPherson, D.W.; Knapp, F. F.

doi:10.1021/jo961033t

Cited by 15 publications

(1 citation statement)

References 9 publications

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“…Deprotonation destroys the original stereocentre of the mandelic acid, but the t -butyl group attached to the acetal directs alkylation of the enolate to the other face to give the propargyl derivative ( 148 ). Overall this amounts to alkylation with retention of configuration [ 167 ]. The carboxylic acid ( 149b ) has also been resolved via the α-methylbenzylamine salt [ 168 ].…”

Section: Muscarinic Antagonistsmentioning

confidence: 99%

Muscarinic Receptor Agonists and Antagonists

2001

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A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes). Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

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Section: Muscarinic Antagonistsmentioning

confidence: 99%

Muscarinic Receptor Agonists and Antagonists

2001

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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

Luo¹,

Beets²,

McAllister³

et al. 1998

J Label Compd Radiopharm

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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.

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Enantiospecific Synthesis of Penehyclidine Hydrochloride and Its Piperidine Derivatives with R Configuration

Han

Chen

et al. 2006

Chin. J. Chem.

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A novel and simple procedure for the enantiospecific synthesis of penehyclidine hydrochloride (8018) isomers and the R configuration derivatives was described. The intramolecular asymmetric cyclization of the monosulfonate of compound 1,2-diol was applied to the execution of the synthesis of the key chiral building block for the first time. The aimed products were obtained with moderate yield in＞99% ee.

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Structure Elucidation Via Stereoselective Synthesis of the Acetate Center of 1-Azabicyclo[2.2.2]oct-3-yl α-Hydroxy- α-(1-iodo-1-propen-3-yl)-α-phenylacetate (IQNP). A High Affinity Muscarinic Imaging Agent for SPECT

Cited by 15 publications

References 9 publications

Muscarinic Receptor Agonists and Antagonists

Muscarinic Receptor Agonists and Antagonists

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

Enantiospecific Synthesis of Penehyclidine Hydrochloride and Its Piperidine Derivatives with R Configuration

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