2β-Carbo[C]methoxy-3β-(3´-(()-2-iodoethenyl)phenyl)nortropane

Serotonin (5-hydroxytryptamine (5HT)) is a neurotransmitter that is transported across the cell membrane by the serotonin transporter (SERT or 5HTT) (1) and is expressed in several tissues of the body, such as those of the brain, lungs (2-4), bone (5, 6), gastrointestinal tract (7), blood platelets (8, 9), and the cardiovascular system (10-12). Within the brain, the SERT is present primarily on the presynaptic neurons (13-15), and a high density of these transporters has been detected in the midbrain, caudate, putamen, thalamus, hypothalamus, midbrain, pons, medulla, and amygdala; by comparison, the cortex has a lower density of the SERT (16-22). Alterations in serotonergic neurotransmission and SERT density in the brain have been implicated in the pathophysiology of depression and schizophrenia and may lead to suicide (23-26). Investigators have developed and evaluated the biological activity of several selective serotonin reuptake inhibitors (SSRIs) for the treatment of these neurological conditions (27-30). Several SSRIs approved by the United States Food and Drug Administration (FDA) are available commercially for the treatment of SERT-related conditions. Positron emission tomography (PET) imaging is often used as an investigational tool to measure the SERT density and SSRI occupancy of the transporter (these are not approved by the FDA as biomarkers) (31-33), and it is considered a suitable technique to study the pathophysiology of depression and to monitor (34) or develop new SERT therapeutics (35-37). In a continuing effort to develop tracer probes for the visualization of SERTs in the clinic with PET imaging techniques, Stehouwer et al. synthesized C-labeled 2β-carbomethoxy-3β-(3´-(()-2-iodoethenyl)phenyl)nortropane ([C]ZIENT) and evaluated the radiolabel in non-human primates (38).