Development and Evaluation of Two Potential 5-HT Receptor PET Tracers: [F]ENL09 and [F]ENL10.

The latest addition to the serotonin (5-HT) receptor family is the 5-HT receptor (5-HTR). This receptor has gained interest as a drug target due to its involvement in various disorders such as depression or schizophrenia. There is currently no clinically validated positron emission tomography (PET) tracer for the 5-HTR available. But, the (arylpiperazinyl-butyl)oxindole scaffold provides a promising lead structure for this purpose. Here, we synthesized 12 (arylpiperazinyl-butyl)oxindole derivatives and in vitro affinity screening identified two structures with suitable affinity and selectivity to be radiolabeled and tested as 5-HTR selective PET tracers. Next, the radiolabeled products [F]ENL09 and [F]ENL10 were evaluated as PET tracers in rats. Both tracers were found to be P-gp substrates, but after P-gp inhibition the brain uptake showed a regional distribution in line with the known 5-HTR distribution.  The [F]ENL10 brain binding was displaceable with a 5-HTR selective ligand, whereas [F]ENL09 was not. We find that [F]ENL10 is a promising 5-HTR selective PET tracer candidate that should be investigated in higher species.