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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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2β-Carbo[11C]methoxy-3β-(4´-((Z)-2-iodoethenyl)phenyl)nortropane

[11C]pZIENT

, PhD and , PhD.

Author Information
, PhD
Department of Radiology,
Center for Systems Imaging,
Emory University
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894

Created: ; Last Update: March 31, 2011.

Chemical name:2β-Carbo[11C]methoxy-3β-(4´-((Z)-2-iodoethenyl)phenyl)nortropaneimage 115001715 in the ncbi pubchem database
Abbreviated name:[11C]pZIENT
Synonym:
Agent Category:Compound
Target:Serotonin transporter (SERT)
Target Category:Transporter
Method of detection:Positron emission tomography (PET)
Source of signal / contrast:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Non-human primates
Click on the above structure of [11C]pZIENT for additional information in PubChem.

Background

[PubMed]

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 123I-labeled nortropane cocaine analog, 2β-carbomethoxy-3β-(4´-((Z)-2-[123I]iodoethenyl)phenyl)nortropane ([123I]pZIENT), 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, pZIENT was labeled with 11C (to obtain [11C]pZIENT) and its in vitro 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.

Other Sources of Information

Other chapters on serotonin transporters in MICAD

Protein and mRNA sequence of human SERT carrier family 6 member 4 (SLC6A4)

Serotonin reuptake inhibitor clinical trials

SLC6A4 in OMIM (Online Mendelian Inheritance in Man) database

SSRI in PubMed

Synthesis

[PubMed]

[11C]pZIENT was synthesized by O-alkylation of N-(t-butoxycarbonyl)-3β-(4´-((Z)-2-iodoethenyl)phenyl)nortropane-2β-carboxylate using [11C]methyl iodide ([11C]CH3I) in dimethylformamide as described elsewhere (39). The N-Boc group was cleaved with 6 M HCl, and the solution was neutralized. The radiotracer was subsequently purified with semipreparative high-performance liquid chromatography and formulated in a 10% ethanol/0.9% saline solution. Total synthesis time (from end of bombardment) was 45 min with an average radiochemical yield of 45% (n = 10, decay-corrected), an average radiochemical purity of >99%, and an average specific activity range of 11–33 GBq/μmol (0.3–0.9 Ci/μmol) at the time of injection. The octanol/water partition coefficient (40-43) for [123I]pZIENT was earlier reported to be 1.6 (38).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The in vitro binding affinities of ZIENT for the SERT, the dopamine transporter (DAT), and the norepinephrine transporter (NET) were determined by Plisson et al. with competition binding assays (39) using a method described earlier by Owens et al. (30). With 3H-citalopram, 125I-RTI-55, and 3H-nisoxetine as ligands for the SERT, DAT, and NET, respectively, ZIENT was shown to have a high affinity for the SERT (Ki = 0.04 ± 0.01 nM) and lower affinities for the DAT (Ki = 15 ± 1.4 nM; ~375-fold lower) and NET (Ki = 24.0 nM; ~600-fold lower).

Animal Studies

Rodents

[PubMed]

No publications are currently available.

Other Non-Primate Mammals

[PubMed]

No publications are currently available.

Non-Human Primates

[PubMed]

MicroPET imaging studies were performed in an anesthetized cynomolgus monkey (n = 1) by injecting the animal with [11C]pZIENT through the antecubital vein (39). A high uptake of the label was observed in the SERT-rich regions of the brain, and peak uptake was achieved 65–75 min postinjection (p.i.). Little washout of the tracer from the SERT-rich regions was noted up to 125 min p.i. The putamen/cerebellum, midbrain/cerebellum, caudate/cerebellum, thalamus/cerebellum, medulla/cerebellum and the pons/cerebellum label uptake ratios at 125 min p.i. were 1.9, 1.9, 1.8, 1.7, 1.4, and 1.3, respectively. Chase studies with (R/S)-citalopram•HBr (1.5 mg/kg body weight), a SERT-selective ligand, showed that the uptake of [11C]pZIENT in the various SERT-rich regions of the brain was displaced up to ~25% at 120 min p.i. No such tracer displacement was evident in a chase study with RTI-113, a DAT ligand. This study indicated that [11C]pZIENT had a binding specificity for the SERT.

In another study, PET imaging of conscious rhesus monkeys (n = 3) injected with [11C]pZIENT showed a continuous increase of radioactivity in the midbrain, putamen, caudate, and thalamus over the total scan time of 120 min p.i. Peak radioactivity uptake values in the occipital cortex, brainstem, and frontal cortex were observed at ~100 min p.i., and little or no washout of the label was noted from these tissues thereafter. Maximum tracer uptake in the cerebellum was observed at ~70 min p.i., followed by a minor washout of the radiolabel. At 120 min p.i., the midbrain/cerebellum, thalamus/cerebellum, putamen/cerebellum, caudate/cerebellum, brainstem/cerebellum, occipital cortex/cerebellum, and frontal cortex/cerebellum uptake ratios were 2.0, 2.0, 1.9, 1.8, 1.6, 1.5, and 1.2, respectively.

Because [11C]pZIENT generated high SERT-rich brain region/cerebellum ratios in conscious non-human primates, the investigators concluded that this radiolabeled compound should be further developed as a radioligand for the quantification of SERT sites with PET imaging (39).

Human Studies

[PubMed]

No publications are currently available.

Supplemental Information

[Disclaimers]

No information is currently available.

NIH Support

Funded by a National Institute of Mental Health grant 1-R21-MH-66622-01 and National Institute of Drug Abuse grants DA00517 and DA10344.

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