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 homomeric α7 nAChRs may play a role in the pathophysiology of neuropsychiatric disorders (6-8). α7 nAChRs are highly expressed in the cerebral cortex, hippocampus and subcortical limbic regions, which are involved in learning, memory, and information processing. 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). 4-[¹¹C]Methylphenyl-1,4-diazabicyclo[3.2.2]nonane-4-carboxylate ([¹¹C]CHIBA-1001), a 4-methyl substituted derivative of SSR180711, has been 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 [¹¹C]CHIBA-1001 by methylation of 4-(tributylstannyl)phenyl-1,4-diazabicyclo[3.2.2]nonane-4-carboxylate in the presence of CuCl₂, potassium carbonate, and [¹¹C]methyl iodide in DMF solution. The mixture was heated for 5 min at 70°C, and [¹¹C]CHIBA-1001 was purified with high-performance liquid chromatography. Average radiochemical yield was 9.49 ± 1.45%. The radiochemical purity was >98% with a specific activity of 344 ± 36 GBq/µmol (9.3 ± 1.0 Ci/µmol; n = 12) at the end of synthesis.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Hashimoto et al. (10) reported that CHIBA-1001 and SSR180711 exhibited IC₅₀ values (obtained with the use of [¹²⁵I]α-bungarotoxin) of 24.9 and 45.8 nM in rat brain membranes, respectively. CHIBA-1001 exhibited little affinity for α4β2, α2β4, and α3β4 nAChRs as well as other receptors.

Animal Studies

Human Studies

[PubMed]

[¹¹C]CHIBA-1001 (680 MBq/18.4 mCi, 17 nmol) PET scans with one healthy male subject (48 years old) showed substantial brain accumulation with selective uptake in the regions of the hippocampus, frontal cortex, thalamus, and cerebellum at 10–30 min after injection with gradual washouts (11). In Logan graphical analysis (total distribution volume, V_T), the cerebellum (16.8 ml/g) showed lower binding than the thalamus (21.6 ml/g), amygdale (20.3), putamen (20.0 ml/g), hippocampus (19.7 ml/g), and frontal cortex (18.1 ml/g). The fraction of unchanged [¹¹C]A-582941 in the plasma as determined with high-performance liquid chromatography was 92.2% at 30 min and 81.4% at 60 min after injection.

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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. [PMC free article: PMC2529405] [PubMed: 18800169]

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