Development of PET/SPECT ligands for the serotonin transporter

There is a great need for PET and SPECT ligands with high affinity and selectivity for the serotonin uptake site. These imaging agents would be useful in screening human populations at risk (e.g., individuals exposed to neurotoxic amphetamines such as MDMA and fenfluramine). Moreover, these radioligands would allow the study of serotonergic function in the normal living human brain, and they also would be useful in the examination of altered serotonergic neurotransmission in diseases such as depression and obsessive-compulsive and other neuropsychiatric disorders. Over the past several years, a number of radioligands have been studied in several laboratories for their in vivo binding to 5-HT uptake sites. Although [3H]paroxetine showed promising binding characteristics, conversion of authentic paroxetine into a PET or SPECT tracer turned out to be difficult and has not been achieved yet. Analogs of paroxetine displayed considerable loss of binding affinity and were, therefore, not useful for imaging purposes. For [11C]fluoxetine, [11C]citalopram, and cis-[11C]DDPI, target-to-nontarget (hypothalamus-to-cerebellar) ratios remained less than 2.0:1 over a 90-min period after injection. The most promising PET agents identified today are [11C]RTI-55 and [11C]McN-5652-X. [11C]RTI-55 labels both 5-HT and DA uptake sites. [11C]McN-5652-X is highly selective for 5-HT uptake sites, and its distribution is consistent with the neuroanatomical distribution of the 5-HT uptake site. Because [11C]McN-5652-Z is a racemic mixture of two stereoisomers, of which the (+) isomer (McN-5652-X) binds to the 5-HT uptake site in vivo and the (-) isomer (McN-5652-W) does not, the possibility exists that regional-specific binding can be determined by subtracting nonspecific binding of the (-) isomer from total radioactivity counts obtained with the (+) isomer. [11C]McN-5652-X is the best PET radioligand for the 5-HT uptake site described thus far. This tracer warrants further testing in nonhuman primates. Efforts are underway to obtain an investigational new drug application for use of the tracer in humans. Promising candidates as SPECT imaging agents for the 5-HT uptake site are [123I]RTI-55 and [123I]-iodo-6-nitroquipazine. Both agents are under intense investigation in different laboratories in the United States.