Comparison of (+)-11C-McN5652 and 11C-DASB as Serotonin Transporter Radioligands Under Various Experimental Conditions

The brain serotonin (5-HT) system has been implicated in several neuropsychiatric conditions, including major depression, anxiety, obsessive compulsive disorder, and schizophrenia. Because of the perceived importance of the brain 5-HT system in these diseases, as well as a variety of normal brain functions (e.g., appetite, sleep), there has been considerable interest in developing neuroimaging techniques that permit assessment of 5-HT neurons in the living human brain. To this end, several research teams have developed and evaluated various SPECT and PET radiotracers for measurements of various components of the brain 5-HT system (1-6). With regard to PET, a series of radioligands showing high binding to the 5-HT transporter (SERT) in vitro have been evaluated, but most have been found to have insufficient specificity or selectivity for the SERT in vivo (7). To date, one of the more promising PET SERT radioligands identified is trans-1,2,3,5,6,10-β-hexahydro-6-[4-(methylthio)phenyl[pyrrolo-[2,1-a]isoquinoline ((+)-11C-McN5652). (+)-11C-McN5652 binds selectively to the SERT, and its regional distribution of binding in humans correlates well with the known distribution of the SERT in human brain (8-10). In addition, studies in baboons and humans exposed to the brain 5-HT neurotoxin, (±)-3,4-methylenedioxymethamphetamine (MDMA), show significant reductions in (+)-11C-McN5652 binding (11-13). However, usefulness of (+)-11C-McN5652 may be limited by its nonspecific binding and slow release from specific binding sites (14,15). There have been recent reports that an alternative SERT radioligand,3-11C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile (11C-DASB), holds promise for use as a SERT PET ligand (16,17). Preclinical studies indicate that, like (+)-11C-McN5652, 11C-DASB has high affinity and selectivity for the SERT in vitro and that, in vivo, it shows saturable and selective binding to the SERT in rodents. Also, damage of 5-HT axon terminals with the neurotoxin p-chloroamphetamine is associated with significant reductions in 11C-DASB binding in vivo in rodents, and low concentrations of radioactive metabolites in rat brain relative to the parent compound (17) suggest that this radioligand holds significant potential for use in evaluating the status of the brain SERT in humans. Notably, initial PET studies in humans (18) indicate that 11C-DASB has highly suitable characteristics for evaluating the status of the SERT in clinical settings and that 11C-DASB can successfully detect SERT occupancy by paroxetine and citalopram (19). The purpose of this study was to compare (+)-11C-McN5652 and 11C-DASB as PET ligands of the SERT in nonhuman primates. In particular, we sought to (a) compare binding characteristics of both radioligands to the SERT in a saline-treated baboon (normal SERT density), (b) compare the ability of the 2 radioligands to detect reductions in SERT density induced by the selective 5-HT neurotoxin MDMA, (c) evaluate the capability of both ligands to detect reduced SERT availability after pretreatment with paroxetine, and (d) determine how binding parameters of the 2 radioligands correlate with direct measures of brain 5-HT axonal markers measured ex vivo.