Synthesis and initial evaluation of [11C](R)-RWAY in monkey-a new, simply labeled antagonist radioligand for imaging brain 5-HT1A receptors with PET.

PURPOSE: We aimed to fulfill a need for a radioligand that may be simply labeled with carbon-11 for effective positron emission tomography (PET) imaging of brain 5-HT(1A) receptors.

METHODS: Racemic RWAY (2,3,4,5,6,7-hexahydro-1-[4-[1-[4-(2-methoxyphenyl)piperazinyl]]-2-phenylbutyryl]-1H-azepine) has high affinity for 5-HT(1A) receptors. The enantiomers of RWAY and O-desmethyl-RWAY, synthesized from commercially available materials, were each labeled with carbon-11 by treating the respective O-desmethyl precursor with [(11)C]iodomethane, and injected into rhesus monkey for measurement of regional brain uptake. The 5-HT(1A) selectivity of (R)-[(11)C]RWAY was checked by administering WAY-100635, before and after radioligand administration. Radiometabolites of (R)-[(11)C]RWAY in blood and urine were analyzed by HPLC with partial elucidation of their structures by LC-MS-MS.

RESULTS: (R)-[(11)C]RWAY was a 5-HT(1A) receptor antagonist exhibiting high brain uptake with regional distribution consistent with specific binding to 5-HT(1A) receptors. The similar affinity, (S)-[(11)C]RWAY was a weak partial agonist at 5-HT(1A) receptors exhibiting similar brain peak uptake with much less 5-HT(1A) receptor-specific binding. The maximal ratio in receptor-rich cingulate gyrus to receptor-devoid cerebellum reached 6.4 at 87.5 min after injection of (R)-[(11)C]RWAY. After treatment with WAY-100635 before or after (R)-[(11)C]RWAY administration, radioactivity levels in 5-HT(1A) receptor-rich regions were reduced almost to that in cerebellum. Blood and urine radiometabolites were less lipophilic than parent and were not due to hydrolysis but to ring hydroxylations, oxidation, and dephenylation.

CONCLUSION: (R)-[(11)C]RWAY is simply prepared and an effective antagonist for imaging brain 5-HT(1A) receptors. This radioligand resists hydrolysis in vivo, gives less lipophilic radiometabolites, and warrants further PET studies in human subjects.