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-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1E, and 5-HT_1F.

5-HT_1A 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-HT_1A receptors are involved in the mediation of emotion and the function of the hypothalamus. 5-HT_1A 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-HT_1A receptors.

There have been several studies to develop specific 5-HT_1A 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-HT_1A 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-HT_1A receptors (K_i = 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-HT_1A receptor (8-10). However, [¹¹C]CUMI-101 was shown to be a partial 5-HT_1A agonist and therefore was less efficient in mediating cell function (11, 12). 3-Chloro-4-[¹⁸F]fluorophenyl-(4-fluoro-4-[[(5-methyl-pyrimidin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl)methanone ([¹⁸F]F15599) was evaluated as a PET probe for the 5-HT_1A receptor (13) because unlabeled F15599 was found to be a selective 5-HT_1A agonist with nanomolar affinity for the 5-HT_1A receptor (14).

Synthesis

[PubMed]

The automated radiosynthesis of [¹⁸F]F15599, 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 30 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 ~30%, the specific activity was 85–120 MBq/nmol (2.3–3.2 mCi/nmol) at the end of synthesis (EOS), and the radiochemical purity was >98%. The total synthesis time was 80 min. The log P value for [¹⁸F]F15599 was 1.17 (lipophilic).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Lemoine et al. (13) performed in vitro autoradiography with [¹⁸F]F15599 in rat and cat brains, which showed radioactivity in the cingulate, hippocampus, and raphe nucleus. Little radioactivity was observed in the cerebellum, a region poor in 5-HT_1A receptors. In comparison with [¹⁸F]MPPF (a 5-HT_1A antagonist), the radioactivity levels of [¹⁸F]F15599 were 50%–80% less than those of [¹⁸F]MPPF in the hippocampus and raphe nucleus in both rats and cats. Competition binding studies of WAY100635 (a 5-HT_1A antagonist) and 8-OH-DPAT (a 5-HT_1A agonist) with [¹⁸F]F15599 in rat hippocampus sections were also performed. WAY100635 reduced the binding of [¹⁸F]F15599 by 69% and 76% with 10 nM and 100 nM WAY100635, respectively. 8-OH-DPAT inhibited the binding by 67% and 85% with 10 nM and 100 nM 8-OH-DPAT, respectively. Gpp(NH)p (10 µM, a non-hydrolysable analog of guanosine 5'-triphosphate) inhibited the [¹⁸F]F15599 binding by 70% in the hippocampus (P < 0.05).

Animal Studies

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., Verdurand M., Vacher B., Blanc E., Le Bars D., Newman-Tancredi A., Zimmer L. [18F]F15599, a novel 5-HT1A receptor agonist, as a radioligand for PET neuroimaging. Eur J Nucl Med Mol Imaging. 2010;37(3):594–605. [PubMed: 19789870]

14.

Maurel J.L., Autin J.M., Funes P., Newman-Tancredi A., Colpaert F., Vacher B. High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity. J Med Chem. 2007;50(20):5024–33. [PubMed: 17803293]