2β-Carbomethoxy-3β-(4´-((Z)-2-[123I]iodoethenyl)phenyl)nortropane

Excerpt

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 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 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). Efforts have also been made to develop and evaluate ¹²³I-labeled probes that can be used to study the biology and functions of SERT with single-photon emission tomography (SPECT) (38). However, these SERT tracers either did not exhibit any in vivo activity or were non-selective for the SERT because they also bound to the dopamine transporter (DAT) and/or the norepinephrine transporter (NET) and often produced low signal/background ratios due to slow clearance from the brain.

In a continuing effort to produce radiolabeled compounds that can be used for the non-invasive study of SERT, investigators developed some tropane analogs of cocaine and demonstrated that these compounds had a high selectivity for SERT and exhibited very low affinity for either the DAT or the NET (39, 40). On the basis of these observations, 2β-carbomethoxy-3β-(4´-((Z)-2-iodoethenyl)phenyl)nortropane (pZIENT) was synthesized, characterized in vitro, and labeled with ¹²³I to obtain [¹²³I]pZIENT for evaluation as a possible SPECT imaging agent to detect the SERT in rat and nonhuman primate brains (38, 41).