Synthesis and evaluation of 18F-labeled 5-HT2A receptor agonists as PET ligands

IntroductionThe serotonin 2A receptor (5-HT2AR) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins and processes in the human brain and several 5-HT2AR PET antagonist radioligands are available. In contrast to an antagonist radioligand, an agonist radioligand should be able to image the population of functional receptors, i.e., those capable of inducing neuroreceptor signaling. Recently, we successfully developed and validated the first 5-HT2AR agonist PET tracer, [11C]Cimbi-36, for neuroimaging in humans and herein disclose some of our efforts to develop an 18F-labeled 5-HT2AR agonist PET-ligand.Methods and resultsThree fluorine containing derivatives of Cimbi-36 were synthesized and found to be potent 5-HT2A agonists. 18F-labeling of the appropriate precursors was performed using [18F]FETos, typically yielding 0.2–2.0 GBq and specific activities of 40–120 GBq/μmol. PET studies in Danish landrace pigs revealed that [18F]1 displayed brain uptake in 5-HT2AR rich regions. However, high uptake in bone was also observed. No blocking effect was detected during a competition experiment with a 5-HT2AR selective antagonist. [18F]2 and [18F]3 showed very low brain uptake.ConclusionNone of the investigated 18F-labeled Cimbi-36 derivatives [18F]1, [18F]2 and [18F]3 show suitable tracer characteristics for in vivo PET neuroimaging of the 5-HT2AR. Although for [18F]1 there was reasonable brain uptake, we suggest that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT2AR antagonist.