Evaluation of novel PET ligands (+)N-[11C]methyl-3-piperidyl benzilate ([11C](+)3-MPB) and its stereoisomer [11C](-)3-MPB for muscarinic cholinergic receptors in the conscious monkey brain: A PET study in comparison with [11C]4-MPB

Tsukada, Hideo; Takahashi, Kazuhiro; Miura, Shuichi; Nishiyama, Shingo; Kakiuchi, Takeharu; Ohba, Hideki; Sato, Kengo; Hatazawa, Jun; Okudera, Toshio

doi:10.1002/1098-2396(200102)39:2<182::aid-syn10>3.0.co;2-q

Cited by 37 publications

(16 citation statements)

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“…injection of Tsukada et al, 2001). The autoradiographic technique to measure various receptors is well established with long-lived radiotracers (e.g., 3 H and 14 C, etc.…”

Section: Discussionmentioning

confidence: 99%

“…They were housed in the laboratory with free access to food and water and maintained on a 12-h dark/light cycle in a room with controlled temperature (24 Ϯ 1°C) and humidity (55 Ϯ 5%). This study was conducted in accordance with the Guide for Care (Takahashi et al, 1999;Tsukada et al, 2001 11 C](ϩ)3-MPB, rats were sacrificed, and the brain tissues were rapidly removed for the autoradiography. The brains were cut into 2-mm-thick coronal sections using a brain matrix (Muromachi Co. Ltd., Kyoto, Japan) at room temperature.…”

Section: Methodsmentioning

confidence: 99%

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In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

Maruyama¹,

Tsukada²,

Nishiyama³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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We evaluated the effects of five clinically used antimuscarinic agents for overactive bladder (OAB) treatment on in vivo muscarinic receptor binding in rat brain by quantitative autoradiography. There was a dose-related decrease in in vivo specific (ϩ)N-[11 C]methyl-3-piperidyl benzilate ([ 11 C](ϩ)3-MPB) binding in each brain region of rats 10 min after i.v. injection of oxybutynin, propiverine, solifenacin, and tolterodine. Rank order of the i.v. dose for 50% receptor occupancy (RO 50 ) of antimuscarinic agents in rat brain regions was propiverine Ͼ solifenacin Ͼ tolterodine, oxybutynin. There was a good linear relationship between in vivo (pRO 50 values in the rat hippocampus) and in vitro (pK i values in human M 1 receptors) receptor binding activities of propiverine, solifenacin, and tolterodine. The observed RO 50 value of oxybutynin was approximately five times smaller than the predicted in vitro K i value. The dose ratios of antimuscarinic agents for the brain receptor occupancy (RO 50 ) to the inhibition of carbachol-and volume-induced increases in intravesical pressure (ID 50 ), which reflects in vivo selectivity for the urinary bladder over the brain, were greater for solifenacin, tolterodine, and propiverine than oxybutynin. Darifenacin displayed only a slight decrease in specific [11 C](ϩ)3-MPB binding in the rat brain regions, and it was not dose-related. In conclusion, in vivo quantitative autoradiographic analysis of brain muscarinic receptor occupancy may provide fundamental basis for managing central nervous system (CNS) side effects in antimuscarinic therapy for OAB. It is suggested that in the treatment of OAB, CNS side effects can be avoided by antimuscarinic agents with high selectivity for the urinary bladder over the brain.

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“…injection of Tsukada et al, 2001). The autoradiographic technique to measure various receptors is well established with long-lived radiotracers (e.g., 3 H and 14 C, etc.…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

Maruyama¹,

Tsukada²,

Nishiyama³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

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“…[ 11 C](+)3-MPB (120.6 GBq/μmol) was labeled by N-methylation of nor-compound with [ 11 C]methyl iodide as described previously (Tsukada et al 2001). [N-methyl-3 H]scopolamine methyl chloride ([ 3 H]NMS, 3.03 TBq/mmol) was purchased from PerkinElmer Life Science, Inc. (Boston, MA).…”

Section: Methodsmentioning

confidence: 99%

Noninvasive evaluation of brain muscarinic receptor occupancy of oxybutynin, darifenacin and imidafenacin in rats by positron emission tomography

et al. 2010

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“…Among several cholinergic neuronal systems, reduced central muscarinic ACh receptor (mAChR) has been reported in AD (Terry and Buccafusco, ). We reported the age‐related changes in mAChR with [ 11 C](+)3‐MPB (Tsukada et al, ) in the living brains of monkeys in a conscious state (Tsukada et al, ). Aged monkeys provided impaired working memory performance (Tsukada et al, ), which was impaired by scopolamine, a specific mAChR inhibitor, in young normal monkeys (Yamamoto et al, ).…”

Section: Discussionmentioning

confidence: 99%

Development of novel PET probe [¹¹C](R,R)HAPT and its stereoisomer [¹¹C](S,S)HAPT for vesicular acetylcholine transporter imaging: A PET study in conscious monkey

Nishiyama

Ohba

Kobashi

et al. 2014

Synapse

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Carbon-11-labeled (R,R)trans-8-methyl-2-hydroxy-3-[4-[2-aminophenyl]piperizinyl]-tetralin ([(11)C](R,R)HAPT) and its stereoisomer [(11)C](S,S)HAPT were developed for imaging vesicular acetylcholine transporters (VAChTs), exclusively located in presynaptic cholinergic neurons. Both positron emission tomography (PET) probes were evaluated in the brain of conscious monkey (Macaca mulatta) using high-resolution PET. Time-activity curves (TACs) of [(11)C](R,R)HAPT peaked within 5 min after the injection in all regions except the caudate and putamen, both of which showed peaks around 20 min postinjection. The regional distribution patterns of [(11)C](R,R)HAPT determined as total distribution volume (V(t)) were highest in the putamen, high in the caudate, intermediate in the amygdala, hippocampus, and thalamus, lower in the cingulate gyrus and frontal, temporal, and occipital cortices, and lowest in the cerebellum. In contrast, the distribution and TACs of [(11)C](S,S)HAPT were homogeneous in all regions. The uptake of [(11)C](R,R)HAPT was reduced by 1 mg/kg (-)-vesamicol, a specific VAChT antagonist, in all regions except the cerebellum, but not by 0.1 mg/kg SA4503, a specific sigma-1 receptor agonist. These results well reflect the in vitro affinity assessments using rat cerebral membranes. They also demonstrate that [(11)C](R,R)HAPT is a potential PET probe for noninvasive and quantitative imaging of VAChT in the living brain.

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Evaluation of novel PET ligands (+)N-[11C]methyl-3-piperidyl benzilate ([11C](+)3-MPB) and its stereoisomer [11C](-)3-MPB for muscarinic cholinergic receptors in the conscious monkey brain: A PET study in comparison with [11C]4-MPB

Cited by 37 publications

References 38 publications

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

Noninvasive evaluation of brain muscarinic receptor occupancy of oxybutynin, darifenacin and imidafenacin in rats by positron emission tomography

Development of novel PET probe [¹¹C](R,R)HAPT and its stereoisomer [¹¹C](S,S)HAPT for vesicular acetylcholine transporter imaging: A PET study in conscious monkey

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Evaluation of novel PET ligands (+)N-[11C]methyl-3-piperidyl benzilate ([11C](+)3-MPB) and its stereoisomer [11C](-)3-MPB for muscarinic cholinergic receptors in the conscious monkey brain: A PET study in comparison with [11C]4-MPB

Cited by 37 publications

References 38 publications

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

In Vivo Quantitative Autoradiographic Analysis of Brain Muscarinic Receptor Occupancy by Antimuscarinic Agents for Overactive Bladder Treatment

Noninvasive evaluation of brain muscarinic receptor occupancy of oxybutynin, darifenacin and imidafenacin in rats by positron emission tomography

Development of novel PET probe [11C](R,R)HAPT and its stereoisomer [11C](S,S)HAPT for vesicular acetylcholine transporter imaging: A PET study in conscious monkey

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Development of novel PET probe [¹¹C](R,R)HAPT and its stereoisomer [¹¹C](S,S)HAPT for vesicular acetylcholine transporter imaging: A PET study in conscious monkey