2β-Carbo[C]methoxy-3β-(4´-(()-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, pons, medulla and amygdala; by comparison, a lower density of the SERT is found in the cortex (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 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 earlier studies it was shown that a I-labeled nortropane cocaine analog, 2β-carbomethoxy-3β-(4´-(()-2-[I]iodoethenyl)phenyl)nortropane ([I]ZIENT), had a high affinity for the human SERT and was suitable for the visualization of this transporter in non-human primates with single-photon emission computed tomography (38). In a continuing effort to develop alternate probes and tracers that can generate superior high-resolution images of the transporter, ZIENT was labeled with C (to obtain [C]ZIENT) and its binding selectivity for the SERT was investigated (39). In addition, the investigators used PET to evaluate the tracer for imaging of the transporter in anesthetized cynomolgus monkeys and conscious rhesus monkeys.