The in vitro pharmacology of the beta-adrenergic receptor pet ligand (s)-fluorocarazolol reveals high affinity for cloned beta-adrenergic receptors and moderate affinity for the human 5-HT1A receptor.
BACKGROUND
s-Fluorocarazolol [(S)-FCZ] is the major positron emission tomography (PET) ligand currently used to visualize central beta-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 beta-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 beta-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-HT1A receptor for which (S)-FCZ had high affinity (Ki=34 nM). Interestingly, (R)-FCZ had low affinity for the h5-HT1A receptor (Ki=342 nM).


CONCLUSIONS
The high affinity of (S)-FCZ for the h5-HT1A receptor is not likely to interfere with studies of peripheral beta-adrenergic receptors, since 5-HT1A receptors are expressed at very low levels outside the central nervous system. Indeed, computer simulations predict that even at low ligand concentrations, 5-HT1A 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 beta-adrenergic receptors unless the contribution by 5-HT1A sites can be shown to be negligible.
Roth
B L
BL
Department of Biochemistry, Rm W438, Case Western Reserve University Medical School, 10900 Euclid Avenue, Cleveland, OH 44106-4935, USA. roth@biocserver.cwru.edu
Ernsberger
P
P
Steinberg
S A
SA
Rao
S
S
Rauser
L
L
Savage
J
J
Hufeisen
S
S
Berridge
M S
MS
Muzic
R F
RF
D000319:Adrenergic beta-Antagonists / Q000378:metabolism*; D002227:Carbazoles / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D011412:Propanolamines / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D014055:Tomography, Emission-Computed
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D008024:Ligands; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D011994:Recombinant Proteins; C089702:fluorocarazolol