Development and Evaluation of Two Potential 5-HT 7 Receptor PET Tracers: [ 18 F]ENL09 and [ 18 F]ENL10

The latest addition to the serotonin (5-HT) receptor family is the 5-HT receptor (5-HT R). 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-HT R 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-HT R 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-HT R distribution. The [ F]ENL10 brain binding was displaceable with a 5-HT R selective ligand, whereas [ F]ENL09 was not. We find that [ F]ENL10 is a promising 5-HT R selective PET tracer candidate that should be investigated in higher species.