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[Carbonyl-11C]N-(2-(1-(4-(2-Methoxyphenyl)-piperazinyl)ethyl)-N-pyridinyl)cyclohexanecarboxamide

[Carbonyl-11C]WAY 100635

Created: ; Last Update: February 21, 2007.

Chemical name:[Carbonyl-11C]N-(2-(1-(4-(2-Methoxyphenyl)-piperazinyl)ethyl)-N-pyridinyl) cyclohexanecarboxamideimage 14 in the ncbi pubchem database
Abbreviated name:[Carbonyl-11C]WAY 100635
Synonym:11C-WAY, 11C-WAY 100635
Agent Category:Compound
Target:5-HT1A receptors
Target Category:Receptor-ligand binding
Method of detection:Positron Emission Tomography (PET)
Source of signal:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-human primates
  • Checkbox Humans
Click on the above structure for additional information in PubChem.

Background

[PubMed]

[Carbonyl-11C]N-(2-(1-(4-(2-Methoxyphenyl)-piperazinyl)ethyl)-N-pyridinyl) cyclohexanecarboxamide ([carbonyl-11C]WAY 100635) is a radioligand developed for positron emission tomography (PET) imaging of serotonin-1A (5-HT1A) receptors in the central nervous system (1). It is a selective 5-HT1A antagonist radiotracer labeled with 11C, a positron emitter with a physical t½ of 20.4 min (2).

The serotonin (5-hydroxytryptamine 5-HT) neurotransmission system consists mainly of neurons in the brainstem, with nerve tracts extending from these neurons to many areas of the brain and spinal cord (3). During firing, the neurons release 5-HT, a neurotransmitter that is involved in the modulation of various important physiological functions and behavior, such as thermoregulation, cardiovascular function, aggressive and sexual behavior, mood, appetite, and the sleep–wake cycle (1). The effects of 5-HT are mediated by as many as seven classes of receptor populations (5-HT1 to 5-HT7), and many of which also contain several subtypes (4). There are five receptor subtypes within the G protein-coupled 5-HT1 receptor family, and the 5-HT1A subtype is primarily located in the limbic forebrain (the hippocampus, entorhinal cortex and septum) (1, 4). It appears to function both as presynaptic (somatodendritic) autoreceptors in the raphe nuclei and as postsynaptic receptors in the terminal fields. This receptor subtype is involved in the modulation of emotion and the function of the hypothalamus, and is implicated in the pathogenesis of anxiety, depression, hallucinogenic behavior, motion sickness, dementia, schizophrenia, and eating disorders (5). A radioligand that can be used to assess the in vivo densities of 5-HT1A receptors and their changes may facilitate investigation of the relationship of these receptors to various neuropsychiatric diseases and aid in the design of novel drugs for their treatment.

Many psychiatric drugs modulate serotonergic transmission or specifically target the 5-HT1A receptors (2). Many compounds have been radiolabeled and studied for visualization and quantification of these receptors using PET or single-photon emission computed tomography (SPECT). Selective agonists such as 8-hydroxy-N-N-dipropylaminotetralin (8-OH-DPAT) were initially studied, but because they bind to the relatively few 5-HT1A receptors in the high-affinity state, the higher affinity required in that situation was difficult to achieve (6). WAY 100635 has been developed as a highly selective, silent antagonist (possessing no intrinsic agonist activity) of 5HT1A receptors at both presynaptic and postsynaptic sites (7). The initial radiolabel was placed in the O-methoxy position, but studies have shown that this [O-methyl-11C] radioligand is metabolized by in vivo amide hydrolysis in primates to a lipophilic radiolabeled amine metabolite that can cross the blood-brain barrier with high affinities for both α1-adrenoceptors and 5-HT1A receptors (8, 9). The labeling of WAY 100635 with 11C in its carbonyl position provides the current [carbonyl-11C]WAY 100635 radioligand which avoids the formation of the undesirable radiolabeled metabolite (8, 10).

Synthesis

[PubMed]

There were three reported procedures for preparing [carbonyl-11C]WAY 100635. Pike and colleagues (11, 12) first reported a simple one-pot procedure. WAY 100635 was synthesized by reacting 2-[1-[4-(2-methoxyphenyl)piperazinyl]]-N-(2-pyridyl)-acetamide with lithium aluminum hydride. The purified ligand (23% yield) was then reacted with 11CO2 produced by a cyclotron using an O2/N2 gas target. This procedure had a relatively low radiochemical yield of 0.7%. The procedure was improved and adopted to a remotely controlled production by using immobilized cyclohexylmagnesium chloride as a Grignard reagent in a long polypropylene ubing to trap 11CO2 and to obtain the desired [carbonyl-11C]cyclohexanecarbonyl chloride (by passing thionyl chloride through the tubing) (13). The synthesis time was 45 min, and the radiochemical yield was improved to 3-4% with a >99% radiochemical purity and a specific activity of 192 GBq/µmol (5.24 Ci/µmol) at the end of synthesis (EOS). Hwang et al. (14) reported another improved, one-pot procedure that removed of excess reagents before the final coupling step. They reported a synthesis time of 45 min, a radiochemical yield of 2.5% (1110 ± 481 MBq from 48.1 GBq; 30 ± 13 mCi from 1.3 Ci 11CO2), and a specific activity of 133 ± 70 GBq/µmol (3.6 ± 1.9 Ci/µmol; n = 40) at the EOS.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Forster and colleagues (15) reported that the affinity pIC50 value of WAY 100635 at 5-HT1A sites to rat hippocampal membranes was 8.87 ± 0.14. This represented a >100-fold selectivity relative to binding at other 5-HT receptors. The in vitro localization of [carbonyl-11C]WAY 100635 was studied in postmortem human brain cryosections by incubating the tissue sections with the radioligand for 20 min at room temperature and then processing for whole hemisphere autoradiography (10). The distribution of [carbonyl-11C]WAY 100635 was similar to that of 3H-labeled WAY 100635 ([O-methyl-3H] labeled, Kd = 2.5 nM) with high binding in the hippocampus and neocortex. This binding was blocked by 5-HT1A receptor ligands that included buspirone (a parial 5-HT1A receptor agonist), 5-HT, pindolol (a 5-HT1A receptor antagonist) and 8-OH-DPAT.

Animal Studies

Rodents

[PubMed]

Maeda and colleagues (16) in 2001 used PET imaging and ex vivo autoradiography to measure the effect of endogenous serotonin on the in vivo binding properties of [carbonyl-11C]WAY 100635 (specific activity = 148-370 GBq/µmol; 4-10 Ci/µmol at the EOS) in rats. In one experiment, 5-HT neurons were destroyed by using 5,7-DHT. In another experiment, the in vivo release of 5-HT was modified by either fenfluramine (10 mg/kg dose; increased 5-HT release) or reserpine (5 mg/kg dose; depletion of 5-HT) treatment. In all of these experiments, no significant change in [carbonyl-11C]WAY 100635 (11.1-25.9 MBq/rat; 0.3-0.7 mCi/rat) binding was found in the hippocampus and entorhinal cortex, whereas there was a 40-65% decrease in the raphe nucleus after neuron destruction with 5,7-DHT. It was suggested that this radioligand mainly bound to the postsynaptic 5-HT1A receptors, and the binding was not sensitive to the level of endogenous 5-HT. Hume et al. (17) also used similar techniques to study the in vivo specific binding of [carbonyl-11C]WAY 100635 (10.4 MBq/rat; 0.28 mCi/rat) in rats. Administration of fenfluramine (10 mg/kg) resulted in a slight overall reduction (10-20%; significant at P = 0.01) in the hippocampus binding. They also concluded that only a large change in endogenous agonist concentration would affect [carbonyl-11C]WAY 100635 binding.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

PET imaging studies were performed in cynomolgus monkeys (n = 4) with i.v. administration of 37 MBq (1 mCi) of [carbonyl-11C]WAY 100635 (specific activity, 20-60 GBq/µmol; 0.54-1.62 Ci/µmol at the time of i.v. administration; TOA) (18). The mean ratios of radioactivity for the neocortex and raphe nuclei to the cerebellum were 7.8 and 2.7, respectively. The in vivo competitive binding experiment (homologous) and its subsequent Scatchard plot indicated a 5-HT1A receptor density value of 16.2 pmol/ml for the neocortex and 4.5 pmol/ml for the raphe nuclei. Bindings in these areas were reduced or inhibited by pretreatment with unlabeled WAY 100635, 8-OH-DAT (8 mg/kg), buspirone (5 mg/kg) or pindolol (1 mg/kg).

Osman and colleagues (19) performed PET imaging for 90 min in 6 cynomolgus monkeys that received injections of 37 MBq (1 mCi) of [carbonyl- 11C]WAY 100635 (specific activity, 80 GBq/µmol; 2.16 Ci/µmol at TOA). The maximum radioactivity in the whole brain was about 5% of the injected dose at 2.5 min after injection. Very high radioactivity was observed in the occipital and temporal cortex, and very low radioactivity was found in the thalamus and cerebellum. The ratios of radioactivity in the occipital cortex to the cerebellum varied from 10 to 16. In comparison with published data from the [O-methyl-11C] labeled analog, the distribution of the latter appeared to be consistent with low penetration and retention of polar radioactive metabolities from [carbonyl-11C]WAY 100635. High performance liquid chromatography (HPLC) analyses of plasma samples indicated that carbonyl-labeled 11C-WAY 100635 was rapidly metabolized. Polar metabolites were detected, and the parent radioligand represented about 19% of the radioactivity in the plasma at 47 min. One of the major metabolites was confirmed to be 11C-cyclohexanecarboxylic acid, and other metabolites were found to be more polar.

Human Studies

[PubMed]

Pike et al. (20) in 1995 reported the first PET imaging of healthy volunteers (n = 5), for 20-90 min after injection with [carbonyl-11C]WAY 100635 (222 MBq/10 µg; 6 mCi/10 µg at the TOA). High radioactivity was observed in the entorhinal cortex, frontal cortrex, hypothalamus and insula, and the lowest radioactivity was found in the cerebellum. The ratios of radioactivity at 20 min after injection for the medial temporal cortex, insula and cingulate to the cerebellum were 3.1, 2.7 and 2.0, respectively. In another similar study, they described a kinetic analysis of a 270 MBq (7.29 mCi) dose of [carbonyl-11C]WAY 100635 (specific activity, 75 GBq/µmol; 2.03 Ci/µmol at TOA) to two healthy subjects (21). With the use of a reference tissue compartmental model, the binding potential (BP) of the medial temporal cortex was shown to be 7.8 for both subjects. The analysis of serum showed that the radioligand was rapidly metabolized to very polar radioactive metabolites that could not enter the brain. This observation was confirmed by Osman and colleagues (19) in their studies of 7 healthy volunteers who received injections of 165-416 MBq/4-10 µg (4.5-11.2 mCi/4-10 µg at theTOA) of [carbonyl-11C]WAY 100635, and then PET imaging was used up to 90 min. Radioactivity was mostly observed to be taken up and retained by 5-HT1A receptor-rich regions of the brain. 11C-Cyclohexanecarboxylic acid was identified by plasma sample analysis using HPLC as a significant radioactive metabolite of the radioligand.

A PET imaging study of tracer kinetic modeling of [carbonyl-11C]WAY 100635 in 6 healthy volunteers described a reference tissue model (the cerebellum as the reference tissue) that was relatively simple to use for the radioligand quantification (22). The BP values derived from this model for the medial temporal cortex, insula cortex, cingulated cortex and raphe nucleus were 7.43-7.65, 6.38-6.61, 4.80-4.85, and 3.91-4.52, respectively. Parsey and colleagues (23) confirmed the usefulness of this model with another study in 5 healthy volunteers.

In a 2005 biodistribution and radiation dosimetry study, 6 healthy volunteers received 243 ± 43 MBq (6.57 ± 1.16 mCi) of [carbonyl-11C]WAY 100635 (specific activity, 140 ± 35 MBq/nmol; 3.78 ± 0.95 mCi/nmol at TOA) (24). The data showed that the radioligand was mainly eliminated by the kidneys, and the urinary bladder without catheterization was the critical organ that received the highest mean radiation absorbed dose (0.194 ± 0.0357 mGy/MBq; 718.5 ± 132.2 mrad/mCi). The brain and the kidneys received 0.00369 ± 0.00128 mGy/MBq (13.7 ± 4.7 mrad/mCi) and 0.0348 ± 0.00636 mGy/MBq (128 ± 23.6 mrad/mCi), respectively. The human radiation dose in the kidneys was 6.0 times higher and in the urinary bladder wall was 60.6 times higher than the estimates from rats.

Sargent et al. (25) performed [carbonyl-11C]WAY 100635 PET scans in 25 patients with major depressive disorders. They found that their BP values were significantly reduced across many of the regions examined (the frontal, temporal, and limbic cortexes) in both unmedicated (n = 15) and medicated (with selective serotonin reuptake inhibitors) depressed patients when compared with healthy volunteers (n = 18). No difference was found between the unmedicated and medicated patients that indicated that the reduced [carbonyl-11C]WAY 100635 binding was not changed by selective serotonin reuptake inhibitor treatment. Other studies also found significant reduction of [carbonyl-11C]WAY 100635 binding in patients with recovered depression, late life depression, medial temporal lobe epilepsy, amyotrophic lateral sclerosis, chronic fatigue syndrome, recovered anorexia nervosa, and Parkinson’s disease (26-31).

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