External Imaging of Cerebral Muscarinic Acetylcholine Receptors

Eckelman, W.C.; Rc, Reba; Rzeszotarski, W. J.; Gibson, R.E.; Hill, Thomas C.; Holman, B. Leonard; Budinger, Thomas F.; Conklin, J.L.; Eng, R.; Grissom, MP

doi:10.1126/science.6608148

Cited by 144 publications

(40 citation statements)

References 8 publications

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“…This regional pattern of distribution is consistent with previously reported data (Eckelman et al 1984;Weinberger et al 1991;Sunderland et al 1995;Lee et al 1996). Mean values for [I-123]IQNB binding in nCi/ml per mCi injected dose and for percent occupancy of muscarinic receptors by olanzapine are given in Table 1.…”

Section: Muscarinic Receptor Binding and Occupancysupporting

confidence: 93%

“…Iodoquinuclidinyl benzilate (IQNB) has similar binding properties, and, when iodinated with radioactive iodine-123, [I-123]IQNB can be used as a SPECT ligand to study muscarinic receptors in vivo (Eckelman et al 1984;Weinberger et al 1991;Sunderland et al 1995). Both in vitro and in vivo , (R,S)- [I-123]IQNB binding has been shown to be distributed in accordance with total muscarinic receptor concentration with an absence of subtype selectivity in rat brain McRee et al 1995).…”

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confidence: 99%

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In Vivo Olanzapine Occupancy of Muscarinic Acetylcholine Receptors in Patients with Schizophrenia

Raedler

Knable

Jones

et al. 2000

Neuropsychopharmacology

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Section: Muscarinic Receptor Binding and Occupancysupporting

confidence: 93%

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confidence: 99%

In Vivo Olanzapine Occupancy of Muscarinic Acetylcholine Receptors in Patients with Schizophrenia

Raedler

Knable

Jones

et al. 2000

Neuropsychopharmacology

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“…[I-123]IQNB, the iodinated form of QNB, has been used in SPECT studies for in vivo measurements of muscarinic receptor availability (Eckelman et al, 1984;Weinberger et al, 1991;Sunderland et al, 1995). Using [I-123]IQNB SPECT, our group has previously reported reduced muscarinic receptor availability in unmedicated schizophrenic patients in vivo (Raedler et al, 2003), a finding similar to that of the post-mortem studies.…”

Section: Introductionsupporting

confidence: 72%

Central Muscarinic Acetylcholine Receptor Availability in Patients Treated with Clozapine

Raedler

Knable

Jones

et al. 2003

Neuropsychopharmacol

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Clozapine is the prototypical atypical antipsychotic. In vitro, clozapine antagonizes a broad range of receptors, including dopamine, serotonin and muscarinic acetylcholine receptors. In vivo, receptor occupancy studies have shown moderate dopamine D 2 receptor blockade as well as high serotonin 5HT 2 receptor blockade for clozapine. Using [I-123]IQNB SPECT, we explored the influence of clozapine on muscarinic receptors in vivo. Eight schizophrenia patients underwent a total of 12 [I-123]IQNB SPECT scans after treatment with low to moderate doses of clozapine (mean 210 mg/day, range 50-450 mg/day). Muscarinic receptor availability was determined for basal ganglia, cortex, thalamus, and pons. A group of 12 age-and sex-matched unmedicated schizophrenia patients was used for comparison. Compared to unmedicated patients, [I-123]IQNB binding was lower in all regions in subjects treated with clozapine and decreased with increasing dose. In patients treated with a daily clozapine dose of at least 200 mg (mean 275 7 88 mg/day), these differences were highly significant (po0.003) with mean reductions of muscarinic receptor availability of 45% for basal ganglia, 58% for cortex, 66% for pons, and 79% for thalamus. These preliminary data indicate that reduction of muscarinic receptor availability by clozapine can be measured in vivo and that moderate daily doses are associated with moderate to high reductions of muscarinic receptor availability. These results may explain, at least in part, the lack of extrapyramidal side effects as well as some side effects seen with clozapine.

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“…The relationship in Eq. 31 therefore provides an explanation for the lack of quantitative correlation between receptor density and regional accumulation of iodinated QNB derivatives (23)(24)(25) …”

Section: Resultsmentioning

confidence: 99%

Quantitative in vivo receptor binding III: Tracer kinetic modeling of muscarinic cholinergic receptor binding.

Frey¹,

Hichwa²,

Ehrenkaufer³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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A tracer kinetic method is developed for the in vivo estimation of high-affinity radioligand binding to central nervous system receptors. Ligand is considered to exist in three brain pools corresponding to free, nonspecifically bound, and specifically bound tracer. These environments, in addition to that of intravascular tracer, are interrelated by a compartmental model of in vivo ligand distribution. A mathematical description of the model is derived, which allows determination of regional blood-brain barrier permeability, nonspecific binding, the rate of receptor-ligand association, and the rate of dissociation of bound ligand, from the time courses of arterial blood and tissue tracer concentrations. The term "free receptor density" is introduced to describe the receptor population measured by this method. The technique is applied to the in vivo determination of regional muscarinic acetylcholine receptors in the rat, with the use of [3H]scopolamine. Kinetic estimates of free muscarinic receptor density are in general agreement with binding capacities obtained from previous in vivo and in vitro equilibrium binding studies. In the striatum, however, kinetic estimates of free receptor density are less than those in the neocortex-a reversal of the rank ordering of these regions derived from equilibrium determinations. A simplified model is presented that is applicable to tracers that do not readily dissociate from specific binding sites during the experimental period. In this instance, specific tracer binding may be accurately determined by measuring tissue ligand concentration at a single time point after bolus intravenous injection, providing that regional cerebral blood flow is known. This derivation has potential clinical application, because it will permit construction of quantitative pictorial maps of regional free receptor densities in the human brain by means of positron emission tomographic imaging.The development of single photon and positron emission tomographs for the imaging of tracer distribution in the human brain has made possible the regional determination of several metabolic and physiologic processes under normal as well as pathologic conditions (1, 2 In the present study, these problems have now been overcome, by application of a tracer kinetic approach to in vivo receptor quantitation, with a compartmental model similar to that used in our previous equilibrium experiments. THEORY Tracer is considered to be present in brain samples in free, nonspecifically bound, and specifically bound states, represented by QLE, QNSE, and QSE, respectively. These variables represent chemical amounts of tracer, while the related terms LE, NSE, and SE are tissue concentrations of tracer and are related to the former terms by the distribution volumes of the compartments VLE, VNSE, and VSE as follows:where C, Q, and V are the tracer concentrations, amounts, and distribution volumes, respectively. For the purposes of the following derivation, the distribution volumes of the brain compartments are assumed ...

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External Imaging of Cerebral Muscarinic Acetylcholine Receptors

Cited by 144 publications

References 8 publications

In Vivo Olanzapine Occupancy of Muscarinic Acetylcholine Receptors in Patients with Schizophrenia

In Vivo Olanzapine Occupancy of Muscarinic Acetylcholine Receptors in Patients with Schizophrenia

Central Muscarinic Acetylcholine Receptor Availability in Patients Treated with Clozapine

Quantitative in vivo receptor binding III: Tracer kinetic modeling of muscarinic cholinergic receptor binding.

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