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3-Chloro-4-[18F]fluorophenyl-(4-fluoro-4-[[((5-methyl-4-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl)methanone (F13714)

[18F]F13714
, PhD
National Center for Biotechnology Information, NLM, NIH

Created: ; Last Update: October 11, 2012.

Chemical name:3-Chloro-4-[18F]fluorophenyl-(4-fluoro-4-[[((5-methyl-4-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl)methanone (F13714)image 144122565 in the ncbi pubchem database
Abbreviated name:[18F]F13714
Synonym:
Agent category:Compound
Target:5-HT1A serotonin receptor
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:18F
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-primate non-rodent mammals
Click on the above structure for additional information in PubChem.

Background

[PubMed]

5-Hydroxytryptamine (5-HT), commonly known as serotonin, has diverse physiological roles as a neurotransmitter in the central nervous system (1). 5-HT is involved in regulation and modulation of sleep, affective and personality behaviors, and pain. It also is a regulator of smooth muscle function and platelet aggregation. The brain cortical 5-HT system has been implicated in several neuropsychiatric disorders, including major depression, anxiety, schizophrenia, and obsessive-compulsive disorder (2, 3). The effects of 5-HT are mediated by as many as seven classes of receptor populations (5-HT1 to 5-HT7), many of which include several subtypes (4). There are five receptor subtypes within the G-protein–coupled 5-HT1 receptor family: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F.

5-HT1A receptors are abundantly present in the hippocampus, entorhinal cortex, frontal cortex, raphe nucleus, and septum; the lowest densities are observed in the basal ganglia, substantia nigra, and cerebellum (5). Some thalamic and hypothalamic nuclei have intermediate densities. 5-HT1A receptors are involved in the mediation of emotion and the function of the hypothalamus. 5-HT1A receptors are implicated in anxiety, depression, hallucinogenic behavior, motion sickness, and eating disorders (6). Thus, there is a need for selective ligands to investigate the pharmacological role of 5-HT1A receptors.

There have been several studies to develop specific 5-HT1A radioligands [PubMed] for positron emission tomography (PET) imaging, such as [carbonyl-11C]WAY 100635, [18F]FPWAY, and [18F]MPPF. However, none of these antagonists distinguishes between the high- and low-affinity states of the 5-HT1A receptors. The high-affinity state of the receptor is coupled to G-proteins, which mediate cell functions by providing intracellular signals. 2-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione (MMP) was reported to be a potent agonist of 5-HT1A receptors (Ki = 0.15 nM) (7). This led to the development of [O-methyl-11C]MMP ([11C]MMP, also known as [11C]CUMI-101) as a useful tool for in vivo PET imaging of the 5-HT1A receptor (8-10). However, [11C]CUMI-101 was shown to be a partial 5-HT1A agonist and therefore was less efficient in mediating cell function (11, 12). 3-Chloro-4-[18F]fluorophenyl-(4-fluoro-4-[[((5-methyl-4-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl)methanone ([18F]F13714) was evaluated as a PET probe for the 5-HT1A receptor because unlabeled F13714 was found to be a selective 5-HT1A agonist with subnanomolar affinity for the 5-HT1A receptor (13).

Synthesis

[PubMed]

The automated radiosynthesis of [18F]F13714, reported by Lemoine et al. (13), involved standard fluoronucleophilic substitution of the corresponding nitro precursor with K[18F]F/Kryptofix2.2.2 in dimethyl sulfoxide for 10 min at 150°C in an automated radiosynthesis unit, followed by solid-phase extraction with a C18 cartridge. The reported overall radiochemical yield of the radiosynthesis was ~10%, the specific radioactivity was 80–150 MBq/nmol (2.16–4.10 mCi/nmol) at the end of synthesis (EOS), and the radiochemical purity was >98%. The total synthesis time was 90 min. The log D (octanol-water partition coefficient) was 2.2 (lipophilic).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Lemoine et al. (13) performed in vitro autoradiography with [18F]F13714 in rat brains, which showed radioactivity in the cingulate, entorhinal cortex, hippocampus, raphe nucleus, and brain stem. Little radioactivity was observed in the cerebellum. The hippocampus/cerebellum and raphe/cerebellum ratios were 5.5 and 3.3, respectively. Competition binding studies of F13714, WAY100635, and 5-HT with [18F]F13714 in rat hippocampus sections were also performed. F13714 reduced the binding of [18F]F13714 by 28%, 77%, and 85% at 1, 10, and 100 nM F13714, respectively. WAY100635 inhibited the binding by 20%, 66%, and 83% at 1, 10, and 100 nM WAY100635, respectively. 5-HT inhibited the binding by 20%, 30%, and 70% at 1, 10, and 100 nM, respectively. Gpp(NH)p (10 µM, a non-hydrolysable analog of guanosine 5'-triphosphate) inhibited the [18F]F13714 binding by 70% in the cortex and 60% in the hippocampus.

Animal Studies

Rodents

[PubMed]

Ex vivo stability studies (n = 3/group) of [18F]F13714 in rat brain hippocampus were performed after intravenous injection of 55.5 MBq (1.5 mCi) [18F]F13714 (13). [18F]F13714 remained 80%, 90%, 94%, and 91% intact in the hippocampus at 10, 20, 30, and 40 min after injection, respectively.

Other Non-Primate Mammals

[PubMed]

Lemoine et al. (13) performed in vivo PET imaging studies in the brains of two male cats for 90 min after injection of 74 MBq (2 mCi) [18F]F13714. High radioactivity levels were observed in the hippocampus, cingulate cortex, and amygdala. The cingulate cortex/cerebellum, amygdala/cerebellum, and hippocampus/cerebellum ratios were 1.5, 1.4, and 1.2, respectively. Pretreatment with WAY100635 (1 mg/kg, 30 min) decreased the cingulate cortex/cerebellum, amygdala/cerebellum, and hippocampus/cerebellum ratios to 1.2, 12, and 1.0, respectively.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

References

1.
Lucki I. The spectrum of behaviors influenced by serotonin. Biol Psychiatry. 1998;44(3):151–62. [PubMed: 9693387]
2.
Fletcher A., Cliffe I.A., Dourish C.T. Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents. Trends Pharmacol Sci. 1993;14(12):41–8. [PubMed: 8122313]
3.
Hoyer D., Clarke D.E., Fozard J.R., Hartig P.R., Martin G.R., Mylecharane E.J., Saxena P.R., Humphrey P.P. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev. 1994;46(2):157–203. [PubMed: 7938165]
4.
Lanfumey L., Hamon M. 5-HT1 receptors. Curr Drug Targets CNS Neurol Disord. 2004;3(1):1–10. [PubMed: 14965240]
5.
Pazos A., Probst A., Palacios J.M. Serotonin receptors in the human brain--III. Autoradiographic mapping of serotonin-1 receptors. Neuroscience. 1987;21(1):97–122. [PubMed: 2955249]
6.
Cowen P.J. Psychopharmacology of 5-HT(1A) receptors. Nucl Med Biol. 2000;27(5):437–9. [PubMed: 10962247]
7.
Kumar J.S., Prabhakaran J., Majo V.J., Milak M.S., Hsiung S.C., Tamir H., Simpson N.R., Van Heertum R.L., Mann J.J., Parsey R.V. Synthesis and in vivo evaluation of a novel 5-HT(1A) receptor agonist radioligand [O-methyl- (11)C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazi ne-3,5(2H,4H)dione in nonhuman primates. Eur J Nucl Med Mol Imaging. 2007;34(7):1050–60. [PubMed: 17221184]
8.
Milak M.S., Severance A.J., Prabhakaran J., Kumar J.S., Majo V.J., Ogden R.T., Mann J.J., Parsey R.V. In vivo serotonin-sensitive binding of [11C]CUMI-101: a serotonin 1A receptor agonist positron emission tomography radiotracer. J Cereb Blood Flow Metab. 2011;31(1):243–9. [PMC free article: PMC3049488] [PubMed: 20571518]
9.
Hines C.S., Liow J.S., Zanotti-Fregonara P., Hirvonen J., Morse C., Pike V.W., Innis R.B. Human biodistribution and dosimetry of (1)(1)C-CUMI-101, an agonist radioligand for serotonin-1a receptors in brain. PLoS One. 2011;6(9):e25309. [PMC free article: PMC3181260] [PubMed: 21980419]
10.
Milak M.S., DeLorenzo C., Zanderigo F., Prabhakaran J., Kumar J.S., Majo V.J., Mann J.J., Parsey R.V. In vivo quantification of human serotonin 1A receptor using 11C-CUMI-101, an agonist PET radiotracer. J Nucl Med. 2010;51(12):1892–900. [PMC free article: PMC3856257] [PubMed: 21098796]
11.
Hendry N., Christie I., Rabiner E.A., Laruelle M., Watson J. In vitro assessment of the agonist properties of the novel 5-HT1A receptor ligand, CUMI-101 (MMP), in rat brain tissue. Nucl Med Biol. 2011;38(2):273–7. [PubMed: 21315283]
12.
Palner M., Underwood M.D., Kumar D.J., Arango V., Knudsen G.M., John Mann J., Parsey R.V. Ex vivo evaluation of the serotonin 1A receptor partial agonist [(3)H]CUMI-101 in awake rats. Synapse. 2011;65(8):715–23. [PubMed: 21108237]
13.
Lemoine L., Becker G., Vacher B., Billard T., Lancelot S., Newman-Tancredi A., Zimmer L. Radiosynthesis and Preclinical Evaluation of 18F-F13714 as a Fluorinated 5-HT1A Receptor Agonist Radioligand for PET Neuroimaging. J Nucl Med. 2012;53(6):969–76. [PubMed: 22577236]
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