Whole-body biodistribution, radiation absorbed dose, and brain SPET imaging with [123I]5-I-A-85380 in healthy human subjects

Fujita, Masahiro; Seibyl, John; Vaupel, Bruce; Tamagnan, Gilles; Early, Michelle; Zoghbi, Sami S.; Baldwin, Ronald M.; Horti, Andrew G.; Koren, Andrei O.; Mukhin, Alexey G.; Khan, Shaukat; Bozkurt, Ali; Kimes, Alane S.; London, Edythe D.; Innis, Robert B.

doi:10.1007/s00259-001-0695-z

Cited by 57 publications

(45 citation statements)

References 11 publications

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“…Studies of non-human primates and humans have examined distributions of nAChRs with these new tracers, and found regional densities of these receptors similar to those in the animal work cited above (Chefer et al, 1999Fujita et al, 2002;Fujita et al, 2003;Kimes et al, 2003;Valette et al, 1999). In initial human studies, no subjective or cardiovascular effects of 2-FA have been reported; however, studies of tobacco dependent subjects have not yet been published.…”

Section: Functional Imaging Of Nicotinic Acetylcholine Receptorsmentioning

confidence: 64%

Functional brain imaging of tobacco use and dependence

Brody

2006

Journal of Psychiatric Research

176

136

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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.

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Section: Functional Imaging Of Nicotinic Acetylcholine Receptorsmentioning

confidence: 64%

Functional brain imaging of tobacco use and dependence

Brody

2006

Journal of Psychiatric Research

176

136

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“…To extend our knowledge concerning the nAChR subtypes in monkey striatum and the effect of nigrostriatal damage on receptor expression, we performed quantitative autoradiography in control and parkinsonian monkey brain using 5 (Sullivan et al, 1996;Villemange et al, 1998;Mukhin et al, 2000;Fujita et al, 2002), although more recent work indicates it may also bind to ␣6* nAChRs (Kulak et al, 2002b). In the present study we examine the effect of ␣-conotoxin MII on binding of [ 125 I]A-85380 to ␤2*-containing nicotinic receptors and extend previous work elucidating the nAChR subtypes affected by nigrostriatal damage in the primate striatum.…”

Section: Atal [mentioning

confidence: 99%

Declines in Different β2* Nicotinic Receptor Populations in Monkey Striatum after Nigrostriatal Damage

Kulak¹,

Musachio²,

McIntosh³

et al. 2002

J Pharmacol Exp Ther

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In the present study we used the nicotinic ligand 5-iodo-A-85380 [5-iodo-3(2(S)-azetidinylmethoxy)pyridine], which selectively binds to ␤2-containing nicotinic acetylcholine receptors, to elucidate the nicotinic receptor subtypes affected by nigrostriatal damage in the monkey. Autoradiographic studies in control monkeys showed that 5- ]epibatidine competition studies extend our earlier studies by demonstrating that the ␣-conotoxin MII-sensitive sites eliminated after moderate nigrostriatal lesioning appear to be composed of two nicotinic receptor subtypes. The data may be important for potential therapeutic approaches because they suggest that there are at least three populations of nicotinic receptors in monkey striatum, of which two are selectively vulnerable to nigrostriatal damage, while the third is more resistant.Extensive evidence now indicates that there are significant declines in central nervous system nicotinic acetylcholine receptors (nAChRs) in Parkinson's disease, a movement disorder characterized by a loss of nigrostriatal dopaminergic neurons (Gotti et al., 1997;Lang and Lozano, 1998;Court et al., 2000;Ball, 2001). Because nAChR deficits may result in decreased activity of neuronal pathways normally involved in the regulation of motor control, there is the potential that receptor agonists may provide a useful therapeutic approach to treat the symptoms of Parkinson's disease (Kelton et al., 2000). In addition, nicotinic agonists may have potential as neuroprotective agents against nigrostriatal degeneration. Epidemiological studies show a very consistent inverse correlation between tobacco use and Parkinson's disease (Morens et al., 1995;Quik and Jeyarasasingam, 2000). Although the active agent in tobacco products that mediates this effect remains to be determined, the finding that nicotine stimulates striatal dopamine release (MacDermott et al., 1999) and is neuroprotective in culture and in animal models (Quik and Jeyarasasingam, 2000) suggests it may be responsible for this apparent neuroprotection.Nicotine exerts its effects on biological systems by interacting with ligand-gated channels composed of five subunits (Wonnacott, 1997;Changeux et al., 1998;Jones et al., 1999;Lukas et al., 1999). Nine nAChR subunits have been isolated from mammalian brain, including the ␣ subunits (␣2-␣7), which contain the cysteines necessary for acetylcholine binding, and the ␤ subunits (␤2-␤4), which are structural subunits contributing to the ligand-binding affinity of the receptor. Although receptors containing the ␣7 subunit appear to form homopentamers in the brain, the other ␣ subunits form receptors in combination with other ␣ subunits or with the ␤ subunits (Luetje and Patrick, 1991;Parker et al., 1998). Since these latter receptors have two ligand-binding sites at ␣/␤ subunit interfaces (Sargent, 1993), there is the potential

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“…Iodine-123-5-IA-85380 ([ 123 I]5-IA; [ 123 I]-5-iodo-3-[2(S)-2-azetidinylmethoxy] pyridine) demonstrates many of the properties necessary for in vivo imaging of β 2 -nAChR with SPECT including high affinity (K D =11 pM), rapid entry into brain, low nonspecific binding, and minimal toxicity [9,10]. The pharmacological specificity of [ 123 I]5-IA for β 2 -nAChRs has been confirmed by the lack of binding in brain of β 2 (-/-) knockout mice [24].…”

Section: Introductionmentioning

confidence: 99%

Age-related decline in nicotinic receptor availability with [123I]5-IA-85380 SPECT

Mitsis

Cosgrove

Staley

et al. 2009

Neurobiology of Aging

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Human postmortem studies have reported decreases with age in high affinity nicotine binding in brain. We investigated the effect of age on β 2 -containing nicotinic acetylcholine receptor (β 2 -nAChR) availability in eight brain regions of living human subjects using the ligand [ 123 I]5-IA-85380 ([ 123 I]5-IA) and single photon emission computed tomography (SPECT). Healthy, nonsmokers (N=47) ranging in age from 18-85 were administered [ 123 I]5-IA using a bolus plus constant infusion paradigm and imaged 6-8 h later under equilibrium conditions. The effect of age on regional β 2 -nAChR availability (V T , regional brain activity/free plasma parent, a measure proportional to the binding potential) was analyzed using linear regression and Pearson's correlation (r). Age and regional β 2 -nAChR availability were inversely correlated in seven of the eight brain regions analyzed, with decline ranging from 32% (thalamus) to 18% (occipital cortex) over the adult lifespan, or up to 5% per decade. These results in living human subjects corroborate postmortem reports of decline in high affinity nicotine binding with age and may aid in elucidating the role of β 2 -nAChRs in cognitive aging.

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Whole-body biodistribution, radiation absorbed dose, and brain SPET imaging with [123I]5-I-A-85380 in healthy human subjects

Cited by 57 publications

References 11 publications

Functional brain imaging of tobacco use and dependence

Functional brain imaging of tobacco use and dependence

Declines in Different β2* Nicotinic Receptor Populations in Monkey Striatum after Nigrostriatal Damage

Age-related decline in nicotinic receptor availability with [123I]5-IA-85380 SPECT

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