2-(2'-((Dimethylamino)methyl)-4'-(3-[18F]fluoropropoxy)-phenylthio)benzenamine

Excerpt

Serotonin (5-hydroxytryptamine, 5-HT) has diverse physiological roles as a neurotransmitter in the central nervous system (1). It is also a regulator of smooth muscle function and platelet aggregation. The brain 5-HT system has been implicated in several neuropsychiatric disorders, including major depression, anxiety, obsessive-compulsive disorder, and schizophrenia (2, 3). The serotonergic transmission is controlled in part by the serotonin transporter (SERT), which regulates the concentration of free, active 5-HT in the synaptic cleft. Citalopram, paroxetine, and fluoxetine were developed as selective SERT inhibitors to treat depression and anxiety disorders by blocking the reuptake of 5-HT [PubMed]. The blockade led to a higher 5-HT concentration in the synaptic cleft and subsequently to improved patient health.

trans-1,2,3,5,6,10-β-Hexahydro-6-[4-([¹¹C]methylthio)phenyl[pyrrolo-[2,1-a]isoquinoline ([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 (4). However, the usefulness of [¹¹C]McN5652 is limited by its nonspecific binding and slow release from specific binding sites (5). [¹¹C]N,N-Dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ([¹¹C]DASB) was found to be a useful tracer for SERT imaging in animals and humans (6-9). It displayed a nanomolar affinity for SERT and a >1,000-fold affinity for SERT over the dopamine transporter (DAT) and the norepinephrine transporter (NET). Uptake in the SERT-rich brain regions was both saturable and selective for SERT. However, the potential widespread use of [¹¹C]DASB is limited by the short half-life of ¹¹C (20 min). 2-(2'-((Dimethylamino)methyl)-4'-(3-fluoropropoxy)-phenylthio)benzenamine was shown to be a selective inhibitor of SERT. 2-(2'-((Dimethylamino)methyl)-4'-(3-[¹⁸F]fluoropropoxy)-phenylthio)benzenamine ([¹⁸F]1) is being evaluated as a useful tool for SERT imaging.