The σ receptors (S1Rs) are implicated in a variety of diseases including Alzheimer disease and cancer. Previous PET S1R radiotracers are characterized by slow kinetics or off-target binding that impedes their use in humans. Here, we report the first PET imaging evaluation in rhesus monkeys of 4 F-labeled spirocyclic piperidine-based PET radiotracers (F- to F-). Baseline scans for the 4 radiotracers were obtained on an adult male rhesus monkey. Blocking scans were obtained with the S1R-selective agonist SA4503 to assess binding specificity ofF- and F- Arterial input functions were measured, and binding parameters were determined with kinetic modeling analysis. In the rhesus brain, all 4 radiotracers showed high and fast uptake. Tissue activity washout was rapid forF- and F-, and much slower for F- and F-, in line with their respective in vitro S1R-binding affinities. Both the 1-tissue-compartment and multilinear analysis-1 kinetic models provided good fits of time-activity curves and reliable estimates of distribution volume. Regional distribution volume values were highest in the cingulate cortex and lowest in the thalamus for all radiotracers. F- showed greater differential uptake across brain regions and 3-fold-higher binding potential than F- SA4503 at the dose of 0.5 mg/kg blocked approximately 85% (F-) and 95% (F-) of radiotracer binding. TracersF- and F- displayed high brain uptake and fast tissue kinetics, with F- having higher specific binding signals than F- in the same monkey. Taken together, these data indicate that both F- and F- possess the requisite kinetic and imaging properties as viable PET tracers for imaging S1R in the human brain.

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A one‐pot synthesis of 1‐alkylidenephthalanes from 3‐(2‐bromophenyl)propyne derivatives has been developed. 3‐(2‐Bromophenyl)propynal acetals 9 and corresponding orthoester 19 were treated successively with n‐butyllithium and various aldehydes and ketones at low temperature to obtain 1‐alkylidenephthalanes 10 and 20 with various functional groups at the exocyclic methylene moiety. Halogen‐metal exchange, nucleophilic addition to various carbonyl compounds, regioselective 5‐exo‐dig cyclization of the respective intermediate lithium alcoholate and hydrolysis represent the key steps in this Domino reaction. A two‐step mechanism involving at first a synchronous cyclization to form a vinyllithium intermediate and then a methoxide elimination leading to the respective 1‐methoxy allenes is suggested based on DFT‐calculations.

Aryl bromides 2a and 2b bearing an alkynyl substituent in the o-position reacted with n-butyllithium and 1-benzylpiperidin-4-one in a one-pot Domino reaction to form ester 3 and aldehyde 5, respectively. Enantiomeric alcohols (R)-8 and (S)-8 were obtained by conjugate NaBH4 reduction of α,β-unsaturated ester 3 in the presence of chiral cocomplexes (R,R)-10 and (S,S)-10. Starting from orthoester 2a, the precursors (R)-8 and (S)-8 for the synthesis of fluspidine enantiomers (R)-1/[18F]­(R)-1 and (S)-1/[18F]­(S)-1 were obtained in only two reaction steps without additional steps for N-protection in an atom-economic manner in 95.6% ee and 97.2% ee, respectively.

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