Sensitivity of [11C]N-methylpyrrolidinyl benzilate ([11C]NMPYB) to endogenous acetylcholine: PET imaging vs tissue sampling methods

Ma, Bing; Sherman, Philip S.; Moskwa, James E.; Koeppe, Robert A.; Kilbourn, Michael R.

doi:10.1016/j.nucmedbio.2003.12.009

Cited by 13 publications

(4 citation statements)

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“…These studies demonstrate that use of a consistent in vivo technique can provide reliable measures of specific binding of radioligands to high affinity sites in the rat brain [17]. Ma et al [18] compared the errors associated with dissection, which has been used for many years, and in vivo imaging studies using a dedicated small animal imager. Treatment with an acetylcholinesterase inhibitor was studied in both awake and isoflurane-anesthetized rats using both ex vivo dissection and in vivo imaging as the analytical tool.…”

Section: Discussionmentioning

confidence: 99%

“…Ex vivo dissection showed a statistically significant 10% inhibition of a radiolabeled muscarinic receptor ligand binding in both awake and anesthetized animals, showing no effect of using isoflurane anesthesia. However, small animal imaging in anesthetized animals failed to successfully demonstrate inhibition of radiotracer binding, most likely due to the increased variation [18]. …”

Section: Discussionmentioning

confidence: 99%

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Imaging of the muscarinic acetylcholine neuroreceptor in rats with the M2 selective agonist [18F]FP-TZTP

Ravasi

Tokugawa

Nakayama³

et al. 2012

Nuclear Medicine and Biology

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Introduction [18F]FP-TZTP is a M2 muscarinic subtype selective receptor-binding radiotracer used in vivo to image human and non-human primate brain following both bolus injection and infusion. In order to carry out repeated studies in rodents, the techniques developed for primates must be transferred to rodents with the same precision. This includes obtaining a metabolite corrected input function. Methods We compared bolus injection with constant infusion in rats that were awake or under isoflurane anesthesia. Brain-plasma and brain-blood distribution ratios were calculated by dividing brain 18F concentrations, determined in vivo by PET imaging with the ATLAS (Advanced Technology Laboratory Animal Scanner), ex vivo by direct counting in excised brain tissue, or quantitative autoradiography, by the plasma or whole blood concentrations that had been corrected for metabolite contents. Results Blood volume constraints prevented adequate blood sampling to define a precise input function after bolus injection thus preventing full kinetic analysis. Constant infusion, however, required fewer blood samples to define the input function allowing calculation of distribution ratios, but complete equilibrium between plasma and tissue had not yet been reached after 120 min. Conclusion Our results showed that the blood clearance and metabolism was too rapid to obtain a reproducible input function after bolus injection. The equilibrium distribution ratios did not lead to precise biochemical parameters but the constant infusion was more suitable in that distribution ratios between tissue and plasma were statistically more precise. Constant infusion is the better approach for studying [18F]FP-TZTP by small animal imaging.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Imaging of the muscarinic acetylcholine neuroreceptor in rats with the M2 selective agonist [18F]FP-TZTP

Ravasi

Tokugawa

Nakayama³

et al. 2012

Nuclear Medicine and Biology

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“…[ 11 C](+)3-MPB was not sensitive to increased endogenous ACh levels following administration of an acetylcholinesterase (AChE) inhibitor, but two related compounds, [ 11 C](+)3-EPB and [ 11 C](+)3-PPB, with lower mAChR affinity, were sensitive to elevations of endogenous ACh provoked by administration of donepezil (250 μg/kg), leading to significantly reduced binding (e.g., for [ 11 C](+)3-PPB ∼19 % in striatum and ∼52 % in frontal cortex) in monkey brain (Nishiyama et al 2001 ; Tsukada et al 2004 ) (Table 4 ). Another subtype non-selective mAChR radioligand, [ 11 C]NMPYB, was found not to be sensitive to ACh in PET studies on rats (Ma et al 2004 ).…”

Section: Current State Of the Art: Imaging Neurotransmitter Changes Umentioning

confidence: 99%

Application of cross-species PET imaging to assess neurotransmitter release in brain

et al. 2015

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RationaleThis review attempts to summarize the current status in relation to the use of positron emission tomography (PET) imaging in the assessment of synaptic concentrations of endogenous mediators in the living brain.ObjectivesAlthough PET radioligands are now available for more than 40 CNS targets, at the initiation of the Innovative Medicines Initiative (IMI) “Novel Methods leading to New Medications in Depression and Schizophrenia” (NEWMEDS) in 2009, PET radioligands sensitive to an endogenous neurotransmitter were only validated for dopamine. NEWMEDS work-package 5, “Cross-species and neurochemical imaging (PET) methods for drug discovery”, commenced with a focus on developing methods enabling assessment of changes in extracellular concentrations of serotonin and noradrenaline in the brain.ResultsSharing the workload across institutions, we utilized in vitro techniques with cells and tissues, in vivo receptor binding and microdialysis techniques in rodents, and in vivo PET imaging in non-human primates and humans. Here, we discuss these efforts and review other recently published reports on the use of radioligands to assess changes in endogenous levels of dopamine, serotonin, noradrenaline, γ-aminobutyric acid, glutamate, acetylcholine, and opioid peptides. The emphasis is on assessment of the availability of appropriate translational tools (PET radioligands, pharmacological challenge agents) and on studies in non-human primates and human subjects, as well as current challenges and future directions.ConclusionsPET imaging directed at investigating changes in endogenous neurochemicals, including the work done in NEWMEDS, have highlighted an opportunity to further extend the capability and application of this technology in drug development.

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“…Skaddan et al [48,100,101] and Ma et al [102] have also developed reversible ligands that monitor changes in acetylcholine resulting from inhibition of mAChE using phenserine. They evaluated a series of 31 compounds to chose the one with optimal properties to measure changes in endogenous acetylcholine.…”

Section: Sensitivity Of Radioligand Binding To Competition With Endogmentioning

confidence: 99%

Imaging of Muscarinic Receptors in the Central Nervous System

Wc¹

2006

CPD

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The development of receptor-binding radiotracers has evolved from a goal of high affinity compounds to give high target to non target ratios to compounds of slightly lesser affinity so that they can reach either steady state after bolus injection or equilibrium after infusion. The other important advance is the ability to measure endogenous neurotransmitter, using various lower affinity muscarinic acetylcholine receptor radioligands. There have been a number of clinical studies that elucidated the mechanism of action of new pharmaceuticals in vivo using external imaging. These include studies of drug interaction of olanzapine, risperidone, clozapine, donepezil, and phenserine with the muscarinic receptor. There have been fewer studies monitoring the effect of therapy in Alzheimer's disease, but those pilot studies give great hope that monitoring therapy is a real possibility. Radioligands for the muscarinic receptor, for ACh esterase, and to measure the concentration of acetylcholine have now been developed, A number of studies in small populations have identified changes in mild to moderate Alzheimer's disease and, perhaps more importantly, changes in radioligand binding have been identified in clinically normal subjects genetically predisposed to Alzheimer's disease by virtue of the epsilon 4+ variant of the APOE gene. Large scale clinical studies are now needed to delineate the true value of these radiotracers in clinical situations. PET and SPECT imaging hold the promise of monitoring the effect of pharmaceuticals in a wide variety of diseases using non-invasive external imaging of the muscarinic cholinergic system.

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Sensitivity of [11C]N-methylpyrrolidinyl benzilate ([11C]NMPYB) to endogenous acetylcholine: PET imaging vs tissue sampling methods

Cited by 13 publications

References 14 publications

Imaging of the muscarinic acetylcholine neuroreceptor in rats with the M2 selective agonist [18F]FP-TZTP

Imaging of the muscarinic acetylcholine neuroreceptor in rats with the M2 selective agonist [18F]FP-TZTP

Application of cross-species PET imaging to assess neurotransmitter release in brain

Imaging of Muscarinic Receptors in the Central Nervous System

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