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4-[76Br]Bromophenyl-1,4-diazabicyclo(3.2.2) nonane-4-carboxylate
[[76Br]SSR180711]

Kam Leung, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD, Email:
24022009SSR180711-76Br
Created: December 12, 2008.
Last Update: February 24, 2009.

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Chemical name:4-[76Br]Bromophenyl-1,4-diazabicyclo(3.2.2) nonane-4-carboxylate
Abbreviated name:[76Br]SSR180711
Synonym:
Agent category:Compound
Target:Neuronal α7 nicotinic acetylcholine receptor (nAChR)
Target category:Receptor
Method of detection:PET
Source of signal:76Br
Activation:No
Studies:

  • In vitro

  • Other Non-primate Mammals

Click on the above structure for additional information in PubChem.

Background

[PubMed]

Neuronal α4β2 nicotinic cholinergic receptors (nAChRs) are part of a heterogeneous family of ligand-gated ion channels expressed in the central nervous system, where their activation by acetylcholine and nicotine causes a rapid increase in cellular permeability to ions, such as Na+ and Ca2+ (1-3). Nicotinic receptors exist as pentamers (homomeric or heteromeric) in various brain regions and ganglia. There are nine subtypes of ligand-binding α receptors (α2 to α10) and four subtypes of structural β receptors (β2 to β5). nAChRs have been found to be involved in cognitive processes such as learning memory and control of movement in normal subjects. nAChR dysfunction has been implicated in a number of human diseases such as schizophrenia, Huntington's disease, Alzheimer's disease, and Parkinson's disease. nAChRs also play a significant role in nicotine addiction and other health problems associated with tobacco smoking.

3-[2(S)-2-Azetidinylmethoxy]pyridine (A-85380) is a highly potent and selective α4β2 nAChR agonist with subnanomolar affinity (4, 5). 6-[18F]Fluoro-A-85380 and 2-[18F]fluoro-A-85380 have been studied in humans as positron emission tomography (PET) agents for α4β2 nAChR imaging in the brain. A-85380 has also been labeled as 5-[123I]iodo-A-85380, which has been developed as a single-photon emission computed tomography agent for the non-invasive study of α4β2 nAChR in the brain. There are some implications that α7 nAChRs may play a role in the pathophysiology of neuropsychiatric disorders (6-8); however, there have been no clinical studies of α7 nAChRs using PET ligands. 4-Bromophenyl-1,4-diazabicyclo(3.2.2) nonane-4-carboxylate (SSR180711) has been shown to be a potent and selective partial agonist for α7 nAChRs with nanomolar affinity (9). [76Br]SSR180711 is being developed as a PET agent for the non-invasive study of α7 nAChR in the brain (10).

Synthesis

[PubMed]

Hashimoto et al. (10) reported the synthesis of [76Br]SSR180711 by bromination of 4-(tributylstannyl)phenyl 2,5-diazabicyclo[3.2.2] nonane-2-carboxylate in the presence of chloramine-T and [76Br]bromide in an ethanol solution. The mixture was heated for 30 min at 75°C. Average radiochemical yield was 16.7 ± 6.14% at the end of synthesis. The radiochemical purity was >99% with a specific activity of 8.11 ± 1.65 GBq/µmol (219 ± 45 mCi/µmol; n = 9) at the end of synthesis.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Biton et al. (9) reported that SSR180711 exhibited inhibition constant (Ki) values (obtained with the use of [3H]α-bungarotoxin) of 22 ± 4 and 14 ± 1 nM in rat and human α7 nAChRs, respectively. On the other hand, SSR180711 exhibited little affinity for α4β2, α2β4, and α3β4 nAChRs as well as other receptors tested.

Animal Studies

Rodents

[PubMed]

No publication is currently available.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

[76Br]SSR180711 PET studies with monkeys (n = 3) showed substantial brain accumulation with selective maximal uptake in the regions of the hippocampus, cortex and basal ganglia (0.010-0.013%dose/cc) 30–40 min after injection with gradual washouts (10); the cerebellum (0.009%dose/cc) showed lower binding than the other brain regions. [76Br]SSR180711 radioactivity level in the brain regions was reduced to the background level of the cerebellum by pretreatment with the α7 nAChR agonist SSR180711 (5.0 mg/kg, 30 min). However, the accumulation of radioactivity in the brain regions after intravenous administration of [76Br]SSR180711 was not affected by pretreatment with the selective α4β2 nAChR agonist A-85380 (1.0 mg/kg, 30 min).

Human Studies

[PubMed]

No publication is currently available.

References
1.
Alkondon M., Albuquerque E.X. The nicotinic acetylcholine receptor subtypes and their function in the hippocampus and cerebral cortex. Prog Brain Res. 2004; 145: 109–20. [PubMed]
2.
Gotti C., Riganti L., Vailati S., Clementi F. Brain neuronal nicotinic receptors as new targets for drug discovery. Curr Pharm Des. 2006; 12(4): 407–28. [PubMed]
3.
Hogg R.C., Raggenbass M., Bertrand D. Nicotinic acetylcholine receptors: from structure to brain function. Rev Physiol Biochem Pharmacol. 2003; 147: 1–46. [PubMed]
4.
Abreo M.A., Lin N.H., Garvey D.S., Gunn D.E., Hettinger A.M., Wasicak J.T., Pavlik P.A., Martin Y.C., Donnelly-roberts D.L., Anderson D.J., Sullivan J.P., Williams M., Arneric S.P., Holladay M.W. Novel 3-Pyridyl ethers with subnanomolar affinity for central neuronal nicotinic acetylcholine receptors. J Med Chem. 1996; 39(4): 817–25. [PubMed]
5.
Sullivan J.P., Donnelly-Roberts D., Briggs C.A., Anderson D.J., Gopalakrishnan M., Piattoni-Kaplan M., Campbell J.E., McKenna D.G., Molinari E., Hettinger A.M., Garvey D.S., Wasicak J.T., Holladay M.W., Williams M., Arneric S.P. A-85380 [3-(2(S)-azetidinylmethoxy) pyridine]: in vitro pharmacological properties of a novel, high affinity alpha 4 beta 2 nicotinic acetylcholine receptor ligand. Neuropharmacology. 1996; 35(6): 725–34. [PubMed]
6.
Gotti C., Zoli M., Clementi F. Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Trends Pharmacol Sci. 2006; 27(9): 482–91. [PubMed]
7.
Nomikos G.G., Schilstrom B., Hildebrand B.E., Panagis G., Grenhoff J., Svensson T.H. Role of alpha7 nicotinic receptors in nicotine dependence and implications for psychiatric illness. Behav Brain Res. 2000; 113(1-2): 97–103. [PubMed]
8.
Nordberg A. Nicotinic receptor abnormalities of Alzheimer's disease: therapeutic implications. Biol Psychiatry. 2001; 49(3): 200–10. [PubMed]
9.
Biton B., Bergis O.E., Galli F., Nedelec A., Lochead A.W., Jegham S., Godet D., Lanneau C., Santamaria R., Chesney F., Leonardon J., Granger P., Debono M.W., Bohme G.A., Sgard F., Besnard F., Graham D., Coste A., Oblin A., Curet O., Vige X., Voltz C., Rouquier L., Souilhac J., Santucci V., Gueudet C., Francon D., Steinberg R., Griebel G., Oury-Donat F., George P., Avenet P., Scatton B. SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (1) binding and functional profile. Neuropsychopharmacology. 2007; 32(1): 1–16. [PubMed]
10.
Hashimoto K., Nishiyama S., Ohba H., Matsuo M., Kobashi T., Takahagi M., Iyo M., Kitashoji T., Tsukada H. [11C]CHIBA-1001 as a novel PET ligand for alpha7 nicotinic receptors in the brain: a PET study in conscious monkeys. PLoS ONE. 2008; 3(9): e3231. [PubMed]
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