The in vitro pharmacology of the β-adrenergic receptor pet ligand (s)-fluorocarazolol reveals high affinity for cloned β-adrenergic receptors and moderate affinity for the human 5-HT_1A receptor

Abstract.

Rationale: s-Fluorocarazolol [(S)-FCZ] is the major positron emission tomography (PET) ligand currently used to visualize central β-adrenergic receptors in vivo, although its pharmacology is incompletely known. Objective: Our objective was to comprehensively characterize the in vitro pharmacology of (S)- and (R)-FCZ to determine its suitability for study of central and peripheral β-adrenergic receptors. Methods: We characterized the in vitro pharmacology of (S)-FCZ at 42 biogenic amine receptors and transporters in vitro using the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. Results: As expected (R)- and (S)-FCZ had high affinities for β-adrenergic receptors (Ki values=0.08–0.45 nM) and negligible affinities (Ki values>100 nM) for nearly all other tested receptors and transporters with the exception of the h5-HT_1A receptor for which (S)-FCZ had high affinity (Ki=34 nM). Interestingly, (R)-FCZ had low affinity for the h5-HT_1A receptor (Ki=342 nM). Conclusion: The high affinity of (S)-FCZ for the h5-HT_1A receptor is not likely to interfere with studies of peripheral β-adrenergic receptors, since 5-HT_1A receptors are expressed at very low levels outside the central nervous system. Indeed, computer simulations predict that even at low ligand concentrations, 5-HT_1A binding in brain regions like hippocampus are likely to be substantial. Thus, (S)-FCZ may not be a suitable PET ligand for studies of central nervous system β-adrenergic receptors unless the contribution by 5-HT_1A sites can be shown to be negligible.