Pharmacological and Toxicological Evaluation of 2-Fluoro-3-(2(<i>S</i>)-azetidinylmethoxy)pyridine (2-F-A-85380), a Ligand for Imaging Cerebral Nicotinic Acetylcholine Receptors with Positron Emission Tomography

Vaupel, D. Bruce; Tella, Srihari R.; Huso, David L.; Wagner, Valentine O.; Mukhin, Alexey G.; Chefer, Svetlana I.; Horti, Andrew G.; London, Edythe D.; Koren, Andrei O.; Kimes, Alane S.

doi:10.1124/jpet.104.073999

Cited by 29 publications

(24 citation statements)

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“…administration of 2-FA in doses up to 10 µmol/kg did not cause death [78]. In pharmacologic and safety studies, [79][80][81] 2-FA showed no mutagenic effect, while 5-IA produced positive effects in one of five bacterial strains in the bacterial reverse mutation assay only with metabolic activation. There was no evidence of gross pathology nor histopathological changes at either acute or subacute toxicity studies in mice with neither compound.…”

Section: Pet Radioligands Based On 3-pyridyl Ethers: Recent Preclmentioning

confidence: 95%

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Horti¹,

Villemagne²

2006

CPD

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Neuronal nicotinic acetylcholine receptors (nAChRs), ubiquitously distributed in the human brain, are implicated in various neurophysiological processes and in the pathophysiology and/or treatment strategies of Alzheimer's and Parkinson's diseases, Tourette's syndrome, epilepsy, schizophrenia, depression, and anxiety, as well as being particularly affected in tobacco dependence/withdrawal. In the past two decades, researchers have developed an extensive series of radioligands for the assessment of nAChRs in vivo through emission tomography, PET and SPECT. Several radioligands, derivatives of A-85380: 2-[(18)F]FA, 6-[(18)F]FA and 5-[(123)I]IA, are now being employed for the evaluation of nAChR in humans with PET and SPECT. Displaying better imaging properties than (11)C-nicotine and a better toxicity profile than epibatidine analogs, they have allowed quantification of thalamic nAChR in the human brain. Nevertheless, A-85380 derivatives still exhibit slow brain kinetics and a moderate signal-to-noise ratio. Current research efforts on the part of PET/SPECT radiochemists, therefore, have focused on development of new, highly specific and highly selective nAChR radioligands with improved brain kinetics that are able to localize high-affinity nAChRs in vivo. Key examples of new PET/SPECT ligands that are derived from several different structural classes are discussed along with a review of their chemical as well as their in vitro and/or in vivo properties. In particular, new PET nAChR radioligands will be examined that either present faster brain kinetics allowing simple and reliable quantification approaches or higher binding potentials suitable for the evaluation of extrathalamic nAChR.

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Section: Pet Radioligands Based On 3-pyridyl Ethers: Recent Preclmentioning

confidence: 95%

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Horti¹,

Villemagne²

2006

CPD

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“…Epibatidine is a broad-spectrum nAChR ligand that binds with very high affinity (25-300 pM) to all known heteromeric nAChRs (Avalos et al, 2002;Houghtling et al, 1995;Xiao and Kellar, 2004). In contrast, [ 3 H]2-FA-85380 binds selectively to b2-containing nAChRs (Brody et al, 2006;Deuther-Conrad et al, 2006;Vaupel et al, 2005). Therefore, examination of the nAChR binding sites labeled by these two ligands in the ventral hippocampus (which is an area important in modulating anxiety responses) and in the cortex (which possesses almost exclusively a4b2 nAChRs) helps to grossly identify Figure 1 Behavioral effects of chronic nicotine and nicotine withdrawal.…”

Section: Chronic In Vivo Treatment Increases Nachrs In the Hippocampumentioning

confidence: 99%

Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal

Turner

Wilkinson

Poole

et al. 2013

Neuropsychopharmacol

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Smoking is the largest preventable cause of death in the United States. Furthermore, a recent study found that o10% of quit attempts resulted in continuous abstinence for 1 year. With the introduction of pharmacotherapies like Chantix (varenicline), a selective a4b2 nicotinic partial agonist, successful quit attempts have significantly increased. Therefore, novel subtype-specific nicotinic drugs, such as sazetidine-A, present a rich area for investigation of therapeutic potential in smoking cessation. The present studies examine the anxietyrelated behavioral and functional effects of the nicotinic partial agonists varenicline and sazetidine-A during withdrawal from chronic nicotine in mice. Our studies indicate that ventral hippocampal-specific infusions of sazetidine-A, but not varenicline, are efficacious in reducing nicotine withdrawal-related anxiety-like phenotypes in the novelty-induced hypophagia (NIH) paradigm. To further investigate functional differences between these partial agonists, we utilized voltage-sensitive dye imaging (VSDi) in ventral hippocampal slices to determine the effects of sazetidine-A and varenicline in animals chronically treated with saline, nicotine, or undergoing 24 h withdrawal. These studies demonstrate a functional dissociation of varenicline and sazetidine-A on hippocampal network activity, which is directly related to previous drug exposure. Furthermore, the effects of the nicotinic partial agonists in VSDi assays are significantly correlated with their behavioral effects in the NIH test. These findings highlight the importance of drug history in understanding the mechanisms through which nicotinic compounds may be aiding smoking cessation in individuals experiencing withdrawal-associated anxiety.

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“…The ability to quantitate nAChRs in vivo using 2-[ 18 F]F-A-85380 has been shown in rats, pigs, rhesus monkeys, baboons, and humans (8,9,16,18,28,53). In addition to the demonstration of specific binding to á 4 â 2 nAChRs in vivo, 2-[ 18 F]F-A-85380 has been demonstrated to be safe, allowing its use in the investigation of disease states in preclinical species and in human (37,55,57).…”

Section: -[ 18 F]f-a-85380mentioning

confidence: 99%

A‐85380: A Pharmacological Probe for the Preclinical and Clinical Investigation of the α₄β₂ Neuronal Nicotinic Acetylcholine Receptor

Rueter¹,

Donnelly‐Roberts²,

Curzon³

et al. 2006

CNS Drug Reviews

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A-85380 [3-(2(s)-azetidinylmethoxy) pyridine] is a neuronal nicotinic acetylcholine receptor (nAChR) agonist that has been a useful tool in the investigation of the function of nAChRs in both preclinical and clinical studies. Amongst nAChR subtypes, A-85380 shows selectivity for the á 4 â 2 vs. the á 7 or á 1 â 1 äã nAChRs. In functional in vitro cation flux assays, A-85380 is a potent and full agonist. A-85380 has a broad-spectrum analgesic profile with efficacy in acute, persistent, and neuropathic pain models. As demonstrated using selective nAChR antagonists or á 4 antisense, the á 4 â 2 nAChR mediates the analgesic effects of A-85380. Interestingly, the site of action depends upon the type of pain as antinociception is mediated by descending inhibition into the spinal cord whereas antiallodynia in neuropathic pain is mediated at both central and peripheral sites. Radiolabelled forms of A-85380 have been developed and shown to be safe for use in vivo in humans. In clinical studies using positron and photon emission tomography, marked decreases in á 4 â 2 nAChRs have been seen in patients with Parkinson's and Alzheimer's disease. Although not developed as a therapeutic agent, A-85380 has proven to be an important component in the development of novel nAChR ligands for the treatment of pain and other disorders.

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Pharmacological and Toxicological Evaluation of 2-Fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-F-A-85380), a Ligand for Imaging Cerebral Nicotinic Acetylcholine Receptors with Positron Emission Tomography

Cited by 29 publications

References 24 publications

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal

A‐85380: A Pharmacological Probe for the Preclinical and Clinical Investigation of the α₄β₂ Neuronal Nicotinic Acetylcholine Receptor

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Pharmacological and Toxicological Evaluation of 2-Fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-F-A-85380), a Ligand for Imaging Cerebral Nicotinic Acetylcholine Receptors with Positron Emission Tomography

Cited by 29 publications

References 24 publications

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

The Quest for Eldorado: Development of Radioligands for In Vivo Imaging of Nicotinic Acetylcholine Receptors in Human Brain

Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal

A‐85380: A Pharmacological Probe for the Preclinical and Clinical Investigation of the α4β2 Neuronal Nicotinic Acetylcholine Receptor

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A‐85380: A Pharmacological Probe for the Preclinical and Clinical Investigation of the α₄β₂ Neuronal Nicotinic Acetylcholine Receptor