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

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11C-Labeled GSK931145

[11C]GSK931145
, PhD
National Center for Biotechnology Information, NLM, Bethesda, MD 20894

Created: ; Last Update: April 19, 2012.

Chemical name:11C-Labeled GSK931145image 134420439 in the ncbi pubchem database
Abbreviated name:[11C]GSK931145
Synonym:
Agent Category:Compound
Target:Glycine transporter 1 (GlyT-1)
Target Category:Transporter
Method of detection:Positron emission tomography (PET)
Source of signal / contrast:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Non-primate non-rodent mammals
  • Checkbox Non-human primates
  • Checkbox Humans
Click on structure for more information in PubChem​.

Background

[PubMed]

The amino acid (aa) glycine acts as a neurotransmitter in the mammalian central nervous system (CNS) and modulates the neuroexcitatory activity of the N-methyl-d-aspartate (NMDA) receptor (NMDAR) through strychnine-insensitive glycine-binding sites located on the receptor (for details regarding the structure and function of NMDAR, see Paoletti et al. (1)). Impaired functioning of the NMDAR is believed to be responsible for the cognitive dysfunction (e.g., loss of reasoning, hallucinations, etc.) observed in individuals suffering from neuropsychiatric ailments, such as schizophrenia and related disorders; improving the activity of this receptor has been shown to be therapeutic (2, 3). Because glycine is an obligatory co-agonist of the NMDAR in the presence of d-serine, the glycine binding site on the receptor is considered to be a suitable therapeutic target for the treatment of schizophrenia (3). Specific sodium chloride–dependent transporters are responsible for transporting glycine into the CNS. However, rapid sequestration into the nerve terminals and surrounding glial cells by two high-affinity transporters, designated as GlyT-1 and GlyT-2, block the activity of glycine on the NMDAR in the synapse (3). GlyT-1 has been shown to maintain low levels of glycine at the synapse, which indicates that the aa controls neurotransmission through the NMDAR (3). It has been hypothesized that inhibition of GlyT-1 would increase glycine concentrations around the synapse, which would enhance the activity of the NMDAR. The use of GlyT-1 inhibitors could be a good approach to treat schizophrenia and other related cognitive afflictions (4). In addition, researchers are interested in using noninvasive imaging techniques to study any changes in the brains of individuals suffering from other neuropsychiatric disorders that may be associated with the GlyT-1. Therefore, several imaging agents, such as [18F]2,4-dichloro-N-((1-(propylsulphonyl)-4-(6-fluoropyridine-2-yl)piperidine-4-yl)methyl)benzamide ([18F]MK-6577 (5)) and [11C]GSK931145 (6-8), that can be used with positron emission tomography (PET) were developed. Among these, [11C]GSK931145 has been successfully evaluated for the in vivo visualization of GlyT-1 in pigs (8), non-human primates, and humans (6, 7).

Synthesis

[PubMed]

GSK931145 was obtained from a commercially supported Neuroscience Center of Excellence in Drug Discovery located in the United Kingdom, and the compound was labeled with 11C as described by Passchier et al. (8). The final labeled product had a radiochemical purity of >99% as determined with high-performance liquid chromatography (HPLC) and a specific activity of >39 GBq/μmol (>1.05 Ci/μmol). The radiochemical yield of the final labeled product was not reported. After purification, [11C]GSK931145 was formulated in normal saline and sterile filtered through a 0.22-μm filter into a vial for use in the different studies.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The pIC50 (-logIC50) values of GSK931145 for the GlyT-1 and GlyT-2 transporters were reported to be 8.4 and 4.6, respectively, indicating that the compound was highly selective for the GlyT-1 transporter (8). The pKi (-logKi) values of GSK931145 in rat cortex was 8.97 (8). The partition coefficient (logD) of the drug was 2.53 (the logD of a drug should be <3 to cross the blood–brain barrier). The brain–blood area under the concentration-time curve ratio for GSK931145 was 1.9 (8).

Animal Studies

Rodents

[PubMed]

No publication is currently available.

Other Non-Primate Mammals

[PubMed]

The suitability of [11C]GSK931145 for the PET imaging of GlyT-1 in anesthetized pigs was evaluated by Passchier et al. (8). The animals (n = 6 pigs) were administered with 372 ± 84.4 MBq (8.83 ± 2.02 mCi) of the labeled compound through the femoral vein, and dynamic PET scans of the brain were acquired from 0 min to 90 min postinjection (p.i.). Blood samples were drawn from the animals at various time points varying from 5 min to 90 min p.i. to investigate metabolic degradation of the tracer. HPLC analysis of the plasma samples on a Phenomenex Sphereclone ODS column showed that ~75% of the labeled compound was metabolized by 60 min p.i. Qualitative analysis of the PET images showed that the radiolabeled probe could enter the brain, and the distribution of radioactivity at 40 min p.i. in the different areas of the organ was mesencephalon (~7.5% of injected dose per gram tissue (% ID/g)) > cerebellum (~6.0% ID/g) > cortex (~5% ID/g), which is consistent with the known distribution of GlyT-1 in the brain. In a blocking study, increasing concentrations of a nonradioactive GlyT-1 inhibitor (GSK565710; 1 μg/kg body weight (BW), 10 μg/kg BW, and 100 μg/kg BW)) were respectively administerd to one pig before the radiolabeled compound was injected into the animal, and PET images were acquired as before. Total volume of distribution estimates (VT) of the brain showed that there was a decrease in VT for different regions of the organ with the increase in dose of GSK565710 (Table 1). This indicated that [11C]GSK931145 bound specifically to the GlyT-1 in these areas of the brain.

Table 1: Total volume of distribution estimates (VT) for [11C]GSK931145 in different regions of the pig brain after the animal was given blocking doses of unlabeled GSK565710

Table

Table 1: Total volume of distribution estimates (VT) for [11C]GSK931145 in different regions of the pig brain after the animal was given blocking doses of unlabeled GSK565710.

Non-Human Primates

[PubMed]

The biodistribution of [11C]GSK931145 was studied in three baboons (Papio anubis) under anesthesia as described by Bullich et al. (6). The animals were given an intravenous injection (i.v.) of the tracer (81 ± 14 MBq (2.19 ± 0.4 mCi); specific activity 30 ± 5.5 GBq/μmol (0.273 ± 0.148 Ci/μmol)), and a series of whole-body PET images were acquired from the primates from 0 min to 80 min p.i. The residence time of radioactivity in the different organs (Table 2) was calculated from the area under the non-decay-corrected time-activity curves divided by the injected activity as described elsewhere (6).

Image

Table

Table 2: Residence time of radioactivity from [11C]GSK931145 in various organs of baboons (n = 3 animals)

From the data (Table 2), it was clear that the maximum residence time of radioactivity was the highest in the liver, followed by the heart, lungs, and brain. This indicated that the main route of clearance for this tracer was through the intestines.

In another study, four baboons were given an i.v. injection of [11C]GSK931145 (105 ± 44 MBq (2.83 ± 1.18 mCi)), and PET images were acquired from the animals for the next 120 min (7). From the images, it was apparent that there was rapid distribution of the tracer in the brain of the animals and that high amounts of radioactivity accumulated in the GlyT-1 rich areas of the organ (brain stem, thalamus, and cerebellum; range of accumulation at 20 min p.i. was ~14% injected dose per liter (% ID/L) to ~12% ID/L) compared with the cortex (has low expression of GlyT-1; accumulation at 20 min p.i. was ~7% ID/L). Prior administration of 0.5 mg/kg BW nonradioactive GSK931145 to the animals (n = 2 baboons) blocked the uptake of radioactivity from [11C]GSK931145 in the GlyT-1–rich areas, and a homogeneous distribution of the tracer was observed in the brain as detailed by Gunn et al. (7). HPLC analysis of the plasma obtained from the animals showed that, on average, ~30% of intact radioligand was present in the arterial plasma at 1 h p.i (7).

Human Studies

[PubMed]

The whole-body distribution of [11C]GSK931145 was investigated in eight healthy human volunteers (6). The individuals were given the tracer through an i.v. injection (average dose was 304.22 ± 112.87 MBq (8.21 ± 3.04 mCi), with an average specific activity of 21.57 ± 7.51 GBq/μmol (0.58 ± 0.20 Ci/μmol)). Whole-body PET scans were acquired from the individuals, and the residence time of radioactivity in the various organs was calculated as detailed by Bullich et al. (Table 3) (6).

Table 3: Residence time of radioactivity from [11C]GSK931145 in various organs of humans (n = 8 individuals)

Table

Table 3: Residence time of radioactivity from [11C]GSK931145 in various organs of humans (n = 8 individuals).

The highest residence time of radioactivity was observed in the liver, followed by the lungs, heart, and brain, and this trend was similar to that observed with the baboons (6). Time-activity curves of the different organs showed there was a gradual loss of radioactivity from all the tissues over a period of 100 min.

In a second study, 13 healthy human volunteers were given an i.v. bolus of 429 ± 158 MBq (11.59 ± 4.3 mCi) [11C]GSK931145, and PET images of the brain were acquired from the individuals for the next 120 min (7). A rapid uptake of radioactivity was observed in the cerebellum, brain stem, and thalamus of the brain of the individuals (each region had ~1.7% ID/L at 40 min p.i.), which was similar to the observations made with the primate brain. In comparison, the cortex showed ~1% ID/L of radioactivity at this time point. When a blocking dose of GSK1018921 (200 mg; a GlyT-1 inhibitor) was administered to the individuals before i.v. injection of [11C]GSK931145, a homogeneous distribution of radioactivity was observed in the brain. The probe was metabolized during the entire duration of the study, and 60 ± 8% of the radioligand was reported to remain intact in the arterial plasma at 1 h p.i. as determined with HPLC (7).

From these studies, the investigators concluded that [11C]GSK931145 can be used for the imaging of GlyT-1 with PET in pigs (8), primates, and humans (7).

Supplemental Information

[Disclaimers]

No information is currently available.

References

1.
Paoletti P. Molecular basis of NMDA receptor functional diversity. Eur J Neurosci. 2011;33(8):1351–65. [PubMed: 21395862]
2.
Shim S.S., Hammonds M.D., Kee B.S. Potentiation of the NMDA receptor in the treatment of schizophrenia: focused on the glycine site. Eur Arch Psychiatry Clin Neurosci. 2008;258(1):16–27. [PubMed: 17901997]
3.
Hashimoto K. Glycine transporter-1: a new potential therapeutic target for schizophrenia. Curr Pharm Des. 2011;17(2):112–20. [PubMed: 21355838]
4.
Wolkenberg S.E., Sur C. Recent progress in the discovery of non-sarcosine based GlyT1 inhibitors. Curr Top Med Chem. 2010;10(2):170–86. [PubMed: 20166956]
5.
Hamill T.G., Eng W., Jennings A., Lewis R., Thomas S., Wood S., Street L., Wisnoski D., Wolkenberg S., Lindsley C., Sanabria-Bohorquez S.M., Patel S., Riffel K., Ryan C., Cook J., Sur C., Burns H.D., Hargreaves R. The synthesis and preclinical evaluation in rhesus monkey of [(1)F]MK-6577 and [(1)(1)C]CMPyPB glycine transporter 1 positron emission tomography radiotracers. Synapse. 2011;65(4):261–70. [PubMed: 20687108]
6.
Bullich S., Slifstein M., Passchier J., Murthy N.V., Kegeles L.S., Kim J.H., Xu X., Gunn R.N., Herance R., Gispert J.D., Gutierrez A., Farre M., Laruelle M., Catafau A.M. Biodistribution and radiation dosimetry of the glycine transporter-1 ligand 11C-GSK931145 determined from primate and human whole-body PET. Mol Imaging Biol. 2011;13(4):776–84. [PubMed: 20730499]
7.
Gunn R.N., Murthy V., Catafau A.M., Searle G., Bullich S., Slifstein M., Ouellet D., Zamuner S., Herance R., Salinas C., Pardo-Lozano R., Rabiner E.A., Farre M., Laruelle M. Translational characterization of [(11) C]GSK931145, a PET ligand for the glycine transporter type 1. Synapse. 2011;65(12):1319–32. [PubMed: 21688322]
8.
Passchier J., Gentile G., Porter R., Herdon H., Salinas C., Jakobsen S., Audrain H., Laruelle M., Gunn R.N. Identification and evaluation of [11C]GSK931145 as a novel ligand for imaging the type 1 glycine transporter with positron emission tomography. Synapse. 2010;64(7):542–9. [PubMed: 20196141]

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