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2β-Carbo(2-[18F]fluoroethoxy)-3β-(4´-((Z)-2-iodoethenyl)phenyl)nortropane

[18F]FEpZIENT

, PhD and , PhD.

Author Information

Created: ; Last Update: March 31, 2011.

Chemical name:2β-Carbo(2-[18F]fluoroethoxy)-3β-(4´-((Z)-2-iodoethenyl)phenyl)nortropane
image 115001713 in the ncbi pubchem database
Abbreviated name:[18F]FEpZIENT
Synonym:
Agent Category:Compound
Target:Serotonin transporter (SERT)
Target Category:Transporter
Method of detection:Positron emission tomography (PET)
Source of signal / contrast:18F
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-human primates
Click on the above structure of [18F]FEpZIENT 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, midbrain, pons, medulla, and amygdala; by comparison, the cortex has a lower density of the transporter (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 are available commercially for the treatment of SERT-related conditions. Positron emission tomography (PET) imaging is often used an investigational tool to measure the SERT density and SSRI occupancy of the transporter (because these are not FDA approved biomarkers) (31-33), and it is considered a suitable technique to study the pathophysiology of depression and to develop (34-36) or monitor (37) the efficacy of new SERT therapeutics.

In a continuing effort to develop tracer probes for the visualization of SERT with PET imaging techniques, Plisson et al. synthesized a 18F-labeled compound, 2β-carbo(2-[18F]fluoroethoxy)-3β-(4´-((Z)-2-iodoethenyl)phenyl)nortropane ([18F]FEpZIENT), and evaluated the radiolabel for the detection of the SERT in Sprague-Dawley rats and non-human primates (38).

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]

[18F]FEpZIENT was synthesized by O-alkylation of N-(t-butoxycarbonyl)-3β-(4´-((Z)-2-iodoethenyl)phenyl)nortropane-2β-carboxylate using [18F]-fluoroethyl brosylate in acetonitrile (39) as described by Plisson et al. (38). The N-Boc group was cleaved with trifluoroacetic acid, 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. The total time of synthesis from the end of bombardment (EOB) was 2 h with an average radiochemical yield of 8% (decay-corrected from EOB), an average radiochemical purity of >99%, and an average specific activity of 296 GBq/μmol (8 Ci/μmol) at the time of injection.

The biodistribution of FEpZIENT was studied in rats using 123I-labeled 2β-carbo(2-fluoroethoxy)-3β-(4´-((Z)-2-iodoethenyl)phenyl)nortropane ([123I]FEpZIENT) (38). The time required to synthesize this radiolabeled compound was ~140 min, and the yield (non–decay-corrected) was 53%. The purity and specific activity of the radioiodinated tracer were not reported.

The octanol/water partition coefficient (40-43) of [18F]FEpZIENT was determined to be 1.80.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The in vitro binding affinities of FEpZIENT for the SERT, the dopamine transporter (DAT), and the norepinephrine transporter (NET) were determined by Plisson et al. with competition binding assays (38) using a method described earlier by Owens et al. (30). Using 3H-citalopram, 125I-RTI-55, and 3H-nisoxetine as the radioligands for the SERT, DAT and NET, respectively, FEpZIENT was shown to have a high affinity for the SERT (Ki = 0.08 ± 0.01 nM) and ~162- and ~350-fold lower affinities for the DAT (Ki = 13.0 ± 2.0 nM) and the NET (Ki = 28.0 ± 5.0 nM), respectively.

Animal Studies

Rodents

[PubMed]

The biodistribution of [123I]FEpZIENT in the rat brain (n = 5 animals per time point) was investigated after an intravenous injection of the tracer to the rodents (38). The accumulation of radioactivity was observed to peak in all parts of the brain by 5 min postinjection (p.i.), and a gradual washout of the tracer was observed for the next 120 min p.i. The hypothalamus/cerebellum, striatum/cerebellum, hippocampus/cerebellum, pons/cerebellum, prefrontal cortex/cerebellum, and occipital cortex/cerebellum label uptake ratios were 2.5, 2.0, 2.0, 1.75, 1.75, and 1.75, respectively. The uptake of radioactivity by the thyroid was observed to increase from 0.06 ± 0.01% injected dose per gram tissue (ID/g) at 5 min to 1.25 ± 0.25% ID/g at 120 min. In a blocking study (n = 3 or 4 rats/group), only (R/S)-citalopram•HBr, (a SERT-selective ligand; 4 or 6 mg/kg body weight (bw)) given 15 min prior to the [123I]FEpZIENT injection was observed to significantly (P value not reported) reduce the incorporation of radioactivity in the SERT-expressing areas (high to moderate) of the rat brain, indicating that [123I]FEpZIENT bound specifically to the SERT.

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) injected with [18F]FEpZIENT through the antecubital vein (38). A high uptake of the label was observed in the SERT-rich regions of the brain (caudate, putamen, thalamus, pons, and medulla), and peak uptake was achieved by ~90 min p.i. This was followed by minimal washout of the tracer from these tissues up to 235 min p.i. Maximum uptake of radioactivity in the midbrain was observed at ~120 min p.i., and very little washout was apparent from this region of the brain until the end of the study. In the cerebellum, the maximum accumulation of radioactivity occurred at ~45 min p.i. followed by a steady washout. The midbrain/cerebellum, putamen/cerebellum, thalamus/cerebellum, medulla/cerebellum, pons/cerebellum, caudate/cerebellum, occipital cortex/cerebellum, and the frontal cortex/cerebellum uptake ratios at 235 min p.i. were 4.4, 3.8, 3.3, 3.3, 3.0, 2.6, 1.6 and 1.5, respectively. In a chase study, the administration of (R/S)-citalopram•HBr (1.5 mg/kg bw) at 120 min p.i. of [18F]FEpZIENT produced a loss of >50% of the label in all the SERT-expressing regions of the monkey brain during the next 120 min. In a similar chase study using RTI-113 (0.3 mg/kg bw; a DAT ligand), no alteration in uptake of the label was apparent. From these studies, the investigators concluded that [18F]FEpZIENT bound selectively to the SERT.

Using a high-resolution research tomograph, PET images were also acquired from a conscious rhesus monkey (n = 1) injected with [18F]FEpZIENT (38). A high uptake of the tracer in the SERT-rich regions of the brain was observed to peak at 75–90 min p.i. The uptake behavior of [18F]FEpZIENT in the conscious monkey was very similar to that observed in the anesthetized animal (see above for details), which suggested that anesthesia did not affect the uptake of [18F]FEpZIENT in these non-human primates (44-47).

From these studies, the investigators concluded that [18F]FEpZIENT was suitable to be developed as a radioligand to study and quantify SERT sites in the brain with PET imaging (38).

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.

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