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[11C]-[N-Methyl]3-[(3-fluorophenyl)sulfonyl]-8-(4-methyl-1-piperazinyl)quinoline

[11C]-GSK215083
, PhD
National Center for Biotechnology Information, NLM, Bethesda, MD 20894

Created: ; Last Update: April 27, 2012.

Chemical name:[11C]-[N-Methyl]3-[(3-fluorophenyl)sulfonyl]-8-(4-methyl-1-piperazinyl)quinolineimage 135631861 in the ncbi pubchem database
Abbreviated name:[11C]-GSK215083
Synonym:
Agent Category:Compound
Target:5-HT6 receptor (5-HT6R)
Target Category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal / contrast:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-primate non-rodent mammals
  • Checkbox Non-human primates
  • Checkbox Humans
Click on above structure for information on [11C]-GSK215083 in PubChem.

Background

[PubMed]

Serotonin (5-hydroxytryptamine; 5-HT), a derivative of the tryptophan amino acid, is a low molecular weight neurotransmitter that plays an important role in the functioning of different physiological, cognitive, and emotional processes. Impairment of the serotonergic system is associated with psychiatric disorders, such as anxiety and depression, and neurological afflictions, such as Parkinson’s disease, Alzheimer’s disease, and epilepsy (1). The 5-HT mediates its biological activity through a group of seven receptors (5-HT1-7R) that are further classified into 14 distinct subtypes on the basis of their structure and pharmacological activity. Except for the 5-HT3R, which is a ligand-gated ion channel, all other 5-HTRs belong to the family of G-protein–coupled seven-transmembrane receptors (2). Radiolabeled tracers have been developed for use with positron emission tomography (PET) to study the different 5-HTR subtypes, and much information is available regarding only the 5-HT1AR, 5-HT1BR, 5-HT2AR, and 5-HT4R subtypes (3). Compared to the discovery of the other 5-HTR subtypes, the identification of 5-HT6R is fairly recent, and this receptor is located mostly in the limbic and cortical regions of the mammalian central nervous system (4). Although the exact mechanism of action of the 5-HT6R is not clear, there are indications that antagonists of this receptor reverse amnesia and improve cognitive and memory functions in individuals suffering from schizophrenia, Parkinson's disease, or Alzheimer’s disease (5). Therefore, it was imperative to develop a ligand that could be used to study the biological characteristics of this receptor.

Radioiodinated SB-258585 ([125I]-SB258585), a selective antagonist of the 5-HT6R, has been shown to have a high affinity for this receptor in membranes derived from rat or pig striatum and human caudate putamen (6). Autoradiography of rat brain sections exposed to [125I]-SB258585 revealed that the 5-HT6R was located primarily in the striatum, followed by the cerebral cortex; accumulation was lowest in the cerebellum of these animals. From this observation, the investigators concluded that the receptor was probably involved in cognition, memory, and locomotor control functions in the animals (7). In another study, [N-methyl]3-[(3-fluorophenyl)sulfonyl]-8-(4-methyl-1-piperazinyl)quinoline (GSK215083) was reported to have a 5-fold and >55-fold higher subnanomolar concentration affinity for the 5-HT6R compared to the concentrations required for the 5-HT2AR and the other 5-HTRs, respectively (3). In addition, the lipophilicity of GSK215083 was determined to be suitable for crossing the blood–brain barrier and penetration into the brain. On the basis of these observations, [11C]-GSK215083 was evaluated in vivo as a 5-HT6R ligand in pigs, non-human primates, and humans (3).

Synthesis

[PubMed]

The synthesis of GSK215083 has been described in a United States patent filed by Ahmed et al. (8). The 11C labeling of the compound has been described by Parker et al. (3). The total time to prepare the tracer was reported to be 40 min from the end of bombardment. The radiochemical yield of the labeling reaction was 35 ± 5%, and the labeled product had a radiochemical purity of >99%. At the end of synthesis, the specific activity of the labeled compound was 414 ± 143 BGq/μmol (11.178 ± 3.86 Ci/μmol) for the preparation used in pigs and non-human primates and 47.4 ± 20.3 GBq/μmol (1.27 ± 0.55 Ci/μmol) for the preparation used in humans.

The synthesis or source of [3H]-GSK215083 used in a rat dosimetry study was not reported (3). The radiochemical purity of the 3H-labeled compound was 99.4%, with a specific activity of 3.07 TBq/mmol (82.9 Ci/mmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

From in vitro studies performed with HeLa cells that stably expressed a recombinant human 5-HT6R, it was determined that GSK215083 had a dissociation constant (Ki) of 0.16 nM for this receptor and that its Ki for the 5-HT2AR was 0.79 nM (~5-fold higher than that for 5-HT6R) (3). For the other 5-HTRs, the Ki of GSK215083 was between 9.1 nM (for 5-HT2BR) and >10,000 nM (for 5-HT7R). From this study, the investigators concluded that GSK215083 could be a suitable ligand for characterization of the 5-HT6R.

The lipophilicity (distribution coefficient, log D) of GSK215083 was determined to be 2.25 ± 0.11, which is considered ideal to allow penetration of the compound into the brain and to study the distribution and characteristics of the 5-HT6R in this organ (3).

Animal Studies

Rodents

[PubMed]

The dosimetry of [3H]-GKS215083 was studied in rats to determine the expected radiation dose to administer to human subjects (3). The animals (the number of animals used in this study was not reported) were given a single bolus of the labeled compound (the route of administration not mentioned), and the rodents were euthanized between 5 min and 120 min postinjection (p.i.) to assess the biodistribution of the tracer in the various tissues. On the basis of the data obtained from this study (data not presented in the publication), it was estimated that a dose of up to 370 MBq [11C]-GSK215083 (mass dose of <10 μg (0.025 μmol)) can be administered to human subjects. This amount of [11C]-GSK215083 would produce a committed effective dose exposure of 8.22 × 10−3 mSv/MBq in humans (3).

Other Non-Primate Mammals

[PubMed]

The in vivo uptake of [11C]-GSK215083 in the brains of two pigs was investigated with PET imaging (3). A baseline PET scan of the animals (under anesthesia) was obtained after an intravenous injection of the high specific activity tracer. Three other sequential scans were performed on the same animals during the day. For these scans, the pigs were injected with escalating doses of non-radioactive GSK215083 (0.005, 0.05, and 0.5 mg/kg body weight) 5 min before the probe was administered to the animals. From the PET images it was evident that maximum uptake of radioactivity was in the striatum region (caudate and putamen areas) of the brain, followed by moderate accumulation in the cortical region, and the lowest amount of tracer was detected in the cerebellum. The uptake of [11C]-GSK215083 in various regions of the brain peaked between 10 min (striatum region) and 20 min p.i. (cortex and cerebellum). There was a slow washout of radioactivity from the striatum, whereas the loss of label from the cortex and the cerebellum was comparatively faster. Blood samples taken from the animals showed that [11C]-GSK215083 was metabolized rapidly in the arterial plasma, and at 35 min p.i. the intact compound comprised only 50% of the total radioactivity as determined with radiographic high-performance liquid chromatography. When the animals were given increasing doses of unlabeled GSK215083 followed by an injection of [11C]-GSK215083, a dose-dependent decrease in specific binding of the radiolabeled compound was observed in the striatum and the cortex regions, whereas the cerebellum showed a relatively small decrease in accumulation of the probe.

Non-Human Primates

[PubMed]

The uptake of [11C]-GSK215083 in the brain of non-human primates (Papio anubis) was investigated as described by Parker et al. (3). A baseline scan from the animals (n = 6 animals; under anesthesia) was acquired after an intravenous injection of the high specific activity tracer. For a second scan later in the day, the animals were first administered unlabeled GSK215083 (0.0002–0.5 mg/kg body weight), and 30 min later the monkeys were injected with the radiolabeled probe. PET images obtained from the scans showed that the uptake of [11C]-GSK215083 in different regions of the brain of these animals peaked between 15 min and 20 min p.i. (accumulation of radioactivity in striatum > cortex > cerebellum). The striatal regions of the monkey brain had the slowest washout of the tracer as observed in the pig study described above.

Human Studies

[PubMed]

The in vivo biodistribution of [11C]-GSK215083 in the brain of healthy human volunteers (n = 4 subjects) was also investigated (3). A baseline PET scan was obtained from each individual after an intravenous bolus injection of the tracer (352 ± 12 MBq (9.5 ± 0.32 mCi)). Peak levels of the radiolabeled compound were observed in the brain of the individuals between 10 min and 20 min p.i. (accumulation of label in striatum > cortex > cerebellum), and the striatal regions showed the slowest washout of the tracer. These observations were similar to those obtained from the pig and monkey studies.

From these studies, it was concluded that [11C]-GSK215083 can be a useful radioligand to investigate 5-HT6R (3). However, the investigators cautioned that because GSK215083 also has a high affinity for 5-HR2AR (the affinity for 5-HT2AR is ~5-fold lower than that for 5-HR6R), data obtained with this tracer will have to be examined carefully for correct interpretation of the results.

Supplemental Information

[Disclaimers]

No information is currently available.

References

1.
Paterson, L.M., B.R. Kornum, D.J. Nutt, V.W. Pike, and G.M. Knudsen, 5-HT radioligands for human brain imaging with PET and SPECT. Med Res Rev, 2011. [PubMed: 21674551]
2.
Hutcheson J.D., Setola V., Roth B.L., Merryman W.D. Serotonin receptors and heart valve disease--it was meant 2B. Pharmacol Ther. 2011;132(2):146–57. [PMC free article: PMC3179857] [PubMed: 21440001]
3.
Parker C.A., Gunn R.N., Rabiner E.A., Slifstein M., Comley R., Salinas C., Johnson C.N., Jakobsen S., Houle S., Laruelle M., Cunningham V.J., Martarello L. Radiosynthesis and Characterization of 11C-GSK215083 as a PET Radioligand for the 5-HT6 Receptor. J Nucl Med. 2012;53(2):295–303. [PubMed: 22223878]
4.
Tassone A., Madeo G., Sciamanna G., Pisani A., Bonsi P. Electrophysiology of 5-HT6 receptors. Int Rev Neurobiol. 2010;94:111–28. [PubMed: 21081204]
5.
Meneses A., Perez-Garcia G., Ponce-Lopez T., Castillo C. 5-HT6 receptor memory and amnesia: behavioral pharmacology--learning and memory processes. Int Rev Neurobiol. 2011;96:27–47. [PubMed: 21329783]
6.
Hirst W.D., Minton J.A., Bromidge S.M., Moss S.F., Latter A.J., Riley G., Routledge C., Middlemiss D.N., Price G.W. Characterization of [(125)I]-SB-258585 binding to human recombinant and native 5-HT(6) receptors in rat, pig and human brain tissue. Br J Pharmacol. 2000;130(7):1597–605. [PMC free article: PMC1572217] [PubMed: 10928963]
7.
Roberts J.C., Reavill C., East S.Z., Harrison P.J., Patel S., Routledge C., Leslie R.A. The distribution of 5-HT(6) receptors in rat brain: an autoradiographic binding study using the radiolabelled 5-HT(6) receptor antagonist [(125)I]SB-258585. Brain Res. 2002;934(1):49–57. [PubMed: 11937069]
8.
Ahmed, M., C.N. Johnson, M.C. Jones, G.J. MacDonald, S.F. Moss, M. Thompson, C.E. Wade, and D. WittyQuinoline derivatives and their use as 5-HT6 ligands. Patent Number 7,977,337 United States Patent and Trademark Office, 2011, Glaox Group Limited USA.
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