Imaging the serotonin transporter with positron emission tomography: initial human studies with [C-11]DAPP and [C-11]DASB

Two novel radioligands, N,N-dimethyl-2-(2-amino-4-methoxyphenyl thio)benzyl amine (DAPP) and (N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine (DA SB), were radiolabeled with carbon-ii and evaluated as in vivo probes of th e serotonin transporter (SERT) using positron emission tomography (PET). Bo th compounds are highly selective, with nanomolar affinity for the serotoni n transporter and micromolar affinity for the dopamine and norepinephrine t ransporters. Six volunteers were imaged twice, once with each of the two ra dioligands. Both ligands displayed very good brain penetration and selectiv e retention in regions rich in serotonin reuptake sites. Both had similar b rain uptake and kinetics, but the cyano analogue, [C-11]DASB, had a slightl y higher brain penetration in all subjects. Plasma analysis revealed that b oth radiotracers were rapidly metabolized to give mainly hydrophilic specie s as determined by reverse-phase high-performance liquid chromatography. In hibition of specific binding to the SERT was demonstrated in three addition al subjects imaged with [C-11]DASB following an oral dose of the selective serotonin reuptake blocker citalopram. These preliminary studies indicate t hat both these substituted phenyl-thiobenzylamines have highly suitable cha racteristics for probing the serotonin reuptake system with PET in humans.