PET analysis of the 5-HT2A receptor inverse agonist ACP-103 in human brain.
The mechanisms underlying the clinical properties of atypical antipsychotics have been postulated to be mediated, in part, by interactions with the 5-HT2A receptor. Recently, it has been recognized that clinically effective antipsychotic drugs are 5-HT2A receptor inverse agonists rather than neutral antagonists. In the present study, which is part of the clinical development of the novel, selective 5-HT2A receptor inverse agonist ACP-103, we applied positron emission tomography (PET) with the radioligand [11C]N-methylspiperone ([11C]NMSP) to study the relationship between oral dose, plasma level, and uptake of ACP-103 in living human brain. The safety of drug administration was also assessed. Four healthy volunteers were examined by PET at baseline, and after the oral administration of various single doses of ACP-103. Two subjects each received 1, 5, and 20 mg doses, and two subjects each received 2, 10, and 100 mg doses, respectively. ACP-103 was well tolerated. Detectable receptor binding was observed at very low ACP-103 serum levels. Cortical [11C]NMSP binding was found to be dose-dependent and fitted well to the law of mass action. A reduction in binding was detectable after an oral dose of ACP-103 as low as 1 mg, and reached near maximal displacement following the 10-20 mg dose. In conclusion, administration of ACP-103 to healthy volunteers was found to be safe and well tolerated, and single oral doses as low as 10 mg were found to fully saturate 5-HT2A receptors in human brain as determined by PET.
Nordstrom
Anna-Lena
AL
Karolinska University Hospital, Department of Clinical Neuroscience, Psychiatry Section, Stockholm, Sweden. anna-lena.nordstrom@ki.se
Mansson
Mattias
M
Jovanovic
Hristina
H
Karlsson
Per
P
Halldin
Christer
C
Farde
Lars
L
Vanover
Kimberly E
KE
Hacksell
Uli
U
Brann
Mark R
MR
Davis
Robert E
RE
Weiner
David M
DM
D000284:Administration, Oral; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D006801:Humans; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D013134:Spiperone / Q000031:analogs & derivatives / Q000378:metabolism; D014508:Urea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D010880:Piperidines; D019275:Radiopharmaceuticals; D044402:Receptor, Serotonin, 5-HT2A; D013134:Spiperone; D014508:Urea; C510793:pimavanserin