In vivo imaging of brain nicotinic acetylcholine receptors with 5-[123I]iodo-A-85380 using single photon emission computed tomography

Chefer, Svetlana I.; Horti, Andrew G.; Lee, Kan Sam; Koren, Andrei O.; Jones, Douglas W.; Gorey, Julia G.; Links, Jonathan M.; Mukhin, Alexey G.; Weinberger, Daniel R.; London, Edythe D.

doi:10.1016/s0024-3205(98)00514-1

Cited by 55 publications

(39 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Radiolabeling of A-85380 was a major advance in imaging nAChRs, because administration of radiolabeled nicotine (used for previous imaging studies) results in high non-specific binding and short drug-receptor interaction times (Sihver et al, 2000). In recent years, 2-[ 18 F]F-A-85380 or simply 2-FA and related compounds (Chefer et al, 1999;Horti et al, 1998;Koren et al, 1998) have been developed for PET imaging, and 5-[ 123/125 I] iodo-A85380 has been used for SPECT imaging (Chefer et al, 1998;Horti et al, 1999;Mukhin et al, 2000) of α 4 β 2 nAChRs.…”

Section: Functional Imaging Of Nicotinic Acetylcholine Receptorsmentioning

confidence: 99%

Functional brain imaging of tobacco use and dependence

Brody

2006

Journal of Psychiatric Research

177

136

View full text Add to dashboard Cite

While most cigarette smokers endorse a desire to quit smoking, only about 14% to 49% will achieve abstinence after 6 months or more of treatment. A greater understanding of the effects of smoking on brain function may (in conjunction with other lines of research) result in improved pharmacological (and behavioral) interventions. Many research groups have examined the effects of acute and chronic nicotine/cigarette exposure on brain activity using functional imaging; the purpose of this paper is to synthesize findings from such studies and present a coherent model of brain function in smokers. Responses to acute administration of nicotine/smoking include: a reduction in global brain activity; activation of the prefrontal cortex, thalamus, and visual system; activation of the thalamus and visual cortex during visual cognitive tasks; and increased dopamine (DA) concentration in the ventral striatum/nucleus accumbens. Responses to chronic nicotine/cigarette exposure include decreased monoamine oxidase (MAO) A and B activity in the basal ganglia and a reduction in α 4 β 2 nicotinic acetylcholine receptor (nAChR) availability in the thalamus and putamen. Taken together, these findings indicate that smoking enhances neurotransmission through cortico-basal ganglia-thalamic circuits either by direct stimulation of nAChRs, indirect stimulation via DA release or MAO inhibition, or a combination of these factors. Activation of this circuitry may be responsible for the effects of smoking seen in tobacco dependent subjects, such as improvements in attentional performance, mood, anxiety, and irritability.

show abstract

Section: Functional Imaging Of Nicotinic Acetylcholine Receptorsmentioning

confidence: 99%

Functional brain imaging of tobacco use and dependence

Brody

2006

Journal of Psychiatric Research

177

136

View full text Add to dashboard Cite

show abstract

“…In summary, the present results demonstrate that 5-iodo-A-85380 is an excellent ligand for studying nAChRs. It features extremely high affinity, slow dissociation from the receptor-ligand complex, high specific-to-nonspecific binding I]iodo-A-85380 in the mouse Vaupel et al, 1998) and rhesus monkey (Chefer et al, 1998) and baboon (Musachio et al, 1999) demonstrated that this radioligand readily crosses the bloodbrain barrier, specifically accumulates in the brain regions enriched with the ␣4␤2 nAChRs, and exhibits low toxicity. These data, together with the results of the present in vitro characterization of 5-iodo-A-85380, suggest that radiolabeled with 123 I, this compound would be particularly promising for noninvasive imaging of nAChRs with single photon emission computed tomography in both animals and humans.…”

Section: Tablementioning

confidence: 99%

“…These properties, together with the results of in vivo studies with this ligand (Chefer et al, 1998;Musachio et al, 1998Musachio et al, , 1999Vaupel et al, 1998) Horti et al, 1999). Specific activity of 5-[…”

mentioning

confidence: 94%

“…Some of these compounds, particularly 5-iodo-A-85380 ( Fig. 1), exhibited extremely high affinity for nAChRs in rat brain Vaupel et al, 1998) and 5-[ 123 I]iodo-A-85380 in rhesus monkey (Chefer et al, 1998) and baboon (Musachio et al, 1999) demonstrated that these radioligands readily crossed the blood-brain barrier, bound to cerebral nAChRs with high specificity, and had low toxicity. Here, we present an in vitro characterization of 5-[…”

mentioning

confidence: 99%

See 1 more Smart Citation

5-Iodo-A-85380, an α4β2 Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors

Mukhin¹,

Gündisch²,

Horti³

et al. 2000

Mol Pharmacol

Self Cite

164

152

View full text Add to dashboard Cite

In an effort to develop selective radioligands for in vivo imaging of neuronal nicotinic acetylcholine receptors (nAChRs), we synthesized 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-iodo-A-85380) and labeled it with 125 I and 123 I. Here we present the results of experiments characterizing this radioiodinated ligand in vitro. The affinity of 5-[ 125 I]iodo-A-85380 for ␣4␤2 nAChRs in rat and human brain is defined by K d values of 10 and 12 pM, respectively, similar to that of epibatidine (8 pM). In contrast to epibatidine, however, 5-iodo-A-85380 is more selective in binding to the ␣4␤2 subtype than to other nAChR subtypes. In rat adrenal glands, 5-iodo-A-85380 binds to nAChRs containing ␣3 and ␤4 subunits with 1/1000th the affinity of epibatidine, and exhibits 1/60th and 1/190th the affinity of epibatidine at ␣7 and muscle-type nAChRs, respectively. Moreover, unlike epibatidine and cytisine, 5-[ 125 I]iodo-A-85380 shows no binding in any brain regions in mice homozygous for a mutation in the ␤2 subunit of nAChRs. Binding of 5-[125 I]iodo-A-85380 in rat brain is reversible, and is characterized by high specificity and a slow rate of dissociation of the receptor-ligand complex (t 1/2 for dissociation ϳ2 h). These properties, along with other features observed previously in in vivo experiments (low toxicity, rapid penetration of the blood-brain barrier, and a high ratio of specific to nonspecific binding), suggest that this compound, labeled with 125 I or 123 I, is superior to other radioligands available for in vitro and in vivo studies of ␣4␤2 nAChRs, respectively.Nicotinic acetylcholine receptors (nAChRs) are excitatory ligand-gated cation channels that are widely distributed in mammalian organisms, appearing in the central and peripheral nervous systems, neuromuscular junctions, and adrenal glands. The nAChR channel complex is composed of five protein subunits, which form a pore that is permeable to Na ϩ , K ϩ , and Ca 2ϩ (Lindstrom, 1995;Holladay et al., 1997).To date, ␣, ␤, ␥, ␦, and ⑀ subunits have been isolated and cloned from mammalian and avian tissues, with nine varieties of ␣ and four varieties of ␤ subunits identified. The ␣1, ␤1, ␥, ␦, and ⑀ subunits form the neuromuscular junction receptor, the very first nAChR to be characterized. The other subunits (␣2-␣9 and ␤2-␤4) are found predominantly throughout the nervous system (Lindstrom, 1995;Holladay et al., 1997). This subunit diversity affords a large potential for a variety of nAChR subtypes, exhibiting distinct cationconducting properties and pharmacological heterogeneity. Based on binding properties and pharmacological sensitivity, major nAChR subtypes in mammalian brain can be categorized as ␣-bungarotoxin-sensitive (␣7) and ␣-bungarotoxin-insensitive (e.g., ␣4␤2) (Lindstrom, 1995;Holladay et al., 1997). Accordingly, 125 I-␣-bungarotoxin has been the radioligand of choice for in vitro characterization of the ␣7 subtype of nAChR, whereas tritiated agonists, such as nico-

show abstract

“…Previously, ␣4␤2* nAChRs were imaged in the human brain using SPECT and (Abreo et al, 1996) and represent a major advancement in the noninvasive imaging of nAChRs over 11 C-labeled nicotine (Chefer et al, 1998;Musachio et al, 1998;Vaupel et al, 1998Vaupel et al, , 2003Horti et al, 1999).…”

Section: -[mentioning

confidence: 99%