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PET Imaging of Muscarinic Receptors

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PET and SPECT of Neurobiological Systems

Abstract

We have successfully developed a novel PET ligand for muscarinic acetylcholine receptors (mAChR), (+)N-[11C]methyl-3-piperidyl benzilate ([11C](+)3-MPB), and evaluated this in the brain of conscious monkeys using high-resolution positron emission tomography (PET). (+)3-MPB had relatively low selectivity to the subtype of mAChR, showing K i values of 1.3, 1.1, 2.8, 1.7, and 5.9 nM for M1, M2, M3, M4, and M5, respectively, of the human receptors. The regional cortical distribution of [11C](+)3-MPB was found to be consistent with mAChR density in the monkey brain as reported in vitro. Time-activity curves of [11C](+)3-MPB peaked in all brain regions, suggesting that this PET probe bound reversibly to the mAChR. Administration of scopolamine, a mAChR antagonist, reduced the radioactivity of [11C](+)3-MPB in all regions except the cerebellum, and the reduction of [11C](+)3-MPB uptake was well correlated with the degree of impairment of working memory performance (R 2 = 0.55 and 0.84 in hippocampus and brainstem, respectively) assessed in conscious monkeys. Based on these preclinical studies, we recently demonstrated in clinical study that chronic fatigue syndrome (CFS) patients with positive serum autoantibody against mAChR showed significantly lower [11C](+)3-MPB binding than negative patients and normal controls. These results demonstrated that PET imaging with [11C](+)3-MPB could be useful for diagnosis of neurological diseases associated with impaired mAChR function and cognitive function.

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References

  • Bodick NC, Offen WW, Levey AI et al (1997) Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol 54:465–473

    Article  CAS  PubMed  Google Scholar 

  • Carson RE, Kiesewetter DO, Jagoda E et al (1998) Muscarinic cholinergic receptor measurements with [18F]FP-TZTP: control and competition studies. J Cereb Blood Flow Metab 18:1130–1142

    Article  CAS  PubMed  Google Scholar 

  • Collerton D (1986) Cholinergic function and intellectual decline in Alzheimer’s disease [Review]. Neuroscience 19:1–28

    Article  CAS  PubMed  Google Scholar 

  • Dannals RF, Långström B, Ravert HT et al (1988) Synthesis of radiotracers for studying muscarinic cholinergic receptors in the living human brain using positron emission tomography: [11C]dexetimide and [11C]levetimide. Appl Radiat Isot 39:291–295

    Article  CAS  Google Scholar 

  • Dewey SL, MacGregor RR, Brondie JD et al (1990a) Mapping muscarinic receptors in human and baboon brain using [N-11C-methyl]benztropine. Synapse 5:213–223

    Article  CAS  PubMed  Google Scholar 

  • Dewey SL, Volkow ND, Logan J et al (1990b) Age-related decrease in muscarinic cholinergic receptor binding in the human brain measured with positron emission tomography (PET). J Neurosci Res 27:569–575

    Article  CAS  PubMed  Google Scholar 

  • Everitt BJ, Robbins TW (1997) Central cholinergic systems and cognition. Annu Rev Psychol 48:649–684

    Article  CAS  PubMed  Google Scholar 

  • Frey KA, Koeppe RA, Mulholland GK et al (1992) In vivo muscarinic cholinergic receptor imaging in human rain with [11C]scopolamine and positron emission tomography. J Cereb Blood Flow Metab 12:147–1541

    Article  CAS  PubMed  Google Scholar 

  • Höhmann C, Antuono P, Coyle JT (1998) Basal forebrain cholinergic neurons and Alzheimer’s disease. In: Iversen LL, Iversen SD, Snyder SD (eds) Psychopharmacology of the aging nervous system. Plenum, New York

    Google Scholar 

  • Hudzik TJ, Wenger GR (1993) Effects of drugs of abuse and cholinergic agents on delayed matching-to-sample responding in the squirrel monkey. J Pharmacol Exp Ther 265:120–127

    CAS  PubMed  Google Scholar 

  • Inglis WL, Olmstead MC, Robbins TW (2001) Selective deficits in attentional performance on the 5-choice serial reaction time task following pedunculopontine tegmental nucleus lesions. Behav Brain Res 123:117–131

    Article  CAS  PubMed  Google Scholar 

  • Irie T, Fukushi K, Namba H et al (1996) Brain acetylcholinesterase activity: validation of a PET tracer in a rat model of Alzheimer’s disease. J Nucl Med 37:649–655

    CAS  PubMed  Google Scholar 

  • Katzman R (1986) Alzheimer’s disease. N Engl J Med 314:964–973

    Article  CAS  PubMed  Google Scholar 

  • Kiesewetter DO, Lee J, Lang L et al (1995) Preparation of 18 F-labeled muscarinic agonist with M2 selectivity. J Med Chem 38:5–8

    Article  CAS  PubMed  Google Scholar 

  • Koeppe RA, Frey KA, Mulholland GK et al (1994) [11C]Tropanyl benzilate binding to muscarinic cholinergic receptors: methodology and kinetic modeling alterations. J Cereb Blood Flow Metab 14:85–99

    Article  CAS  PubMed  Google Scholar 

  • Kozak R, Bowman EM, Latimer MP (2005) Excitotoxic lesions of the pedunculopontine tegmental nucleus in rats impair performance on a test of sustained attention. Exp Brain Res 162:257–264

    Article  PubMed  Google Scholar 

  • Långström B, Antoni G, Gullberg P et al (1986) The synthesis of l-11C-labeled ethyl, propyl, butyl and isobutyl iodides and examples of alkylation reactions. Appl Radiat Isot 37:1141–1145

    Article  Google Scholar 

  • Laruelle M (2000) Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 20:423–451

    Article  CAS  PubMed  Google Scholar 

  • Lee KS, Frey KA, Koeppe RA et al (1996) In vivo quantification of cerebral muscarinic receptors in normal human aging using positron emission tomography and [11C]tropanyl benzilate. J Cereb Blood Flow Metab 16:303–310

    Article  CAS  PubMed  Google Scholar 

  • Logan J, Fowler J, Volkow N et al (1990) Graphical analysis of reversible radioligand binding from time-activity measurements applied to N-11C-methyl-(−)-cocaine PET studies in human subjects. J Neurochem 10:740–747

    CAS  Google Scholar 

  • Mulholland GK, Jewett DW, Otto CA et al (1988a) Synthesis and regional brain distribution of [C-11]N-methyl-4-piperidyl benzilate ([C-11]NMPB) in the rat. J Nucl Med 29:768

    Google Scholar 

  • Mulholland GK, Jewett DW, Toorongian SA (1988b) Routine synthesis of N-[11C-methyl]scopolamine by phosphate mediated reductive methylation with [11C]formaldehyde. Appl Radiat Isot 39:373–379

    Article  CAS  Google Scholar 

  • Mulholland GK, Otto CA, Jewett DW et al (1992) Synthesis, rodent biodistribution, dosimetry, metabolism and monkey images of carbon-11-labeled (+)-2α-tropanyl benzilate: a central muscarinic receptor imaging agent. J Nucl Med 33:423–430

    CAS  PubMed  Google Scholar 

  • Nishimura Y, Onoe H, Morichika Y et al (2007) Time-dependent central compensatory mechanism of finger dexterity after spinal-cord injury. Science 318:1150–1155

    Article  CAS  PubMed  Google Scholar 

  • Nishiyama S, Tsukada H, Sato K et al (2001) Evaluation of PET ligands (+)N-[11C]ethyl-3-piperidyl benzilate and (+)N-[11C]propyl-3-piperidyl benzilate for muscarinic cholinergic receptors: a PET study with microdialysis in comparison with (+)N-[11C]methyl-3-piperidyl benzilate in the conscious monkey brain. Synapse 40:159–169

    Article  CAS  PubMed  Google Scholar 

  • Ohba H, Harada N, Nishiyama S et al (2009) Ketamine/xylazine anesthesia alters [11C]MNPA binding to dopamine D2 receptors and response to methamphetamine challenge in monkey brain. Synapse 63:534–537

    Article  CAS  PubMed  Google Scholar 

  • Onoe H, Inoue O, Suzuki K et al (1994) Ketamine increases the striatal N-11C-methylspiperone binding in vivo: positron emission tomography study using conscious rhesus monkey. Brain Res 663:191–198

    Article  CAS  PubMed  Google Scholar 

  • Onoe H, Komori M, Onoe K et al (2001) Cortical networks recruited for time perception: a monkey positron emission tomography (PET) study. Neuroimage 13:37–45

    Article  CAS  PubMed  Google Scholar 

  • Patlak C, Blasberg RG, Fenstermacher JD (1983) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3:1–7

    Article  CAS  PubMed  Google Scholar 

  • Perry EK (1986) The cholinergic hypothesis – ten years on [Review]. Br Med Bull 42:63–69

    CAS  PubMed  Google Scholar 

  • Podruchny TA, Connolly C, Bokde A et al (2003) In vivo muscarinic 2 receptor imaging in cognitively normal young and older volunteers. Synapse 48:39–44

    Article  CAS  PubMed  Google Scholar 

  • Prenant C, Barre L, Crouzel C (1989) Synthesis of n.c.a. [11C]QNB. J Labelled Compd Radioparm 26:199–201

    Article  Google Scholar 

  • Raedler TJ, Knable MB, Jones DW et al (2003) In vivo determination of muscarinic acetylcholine receptor availability in schizophrenia. Am J Psychiatry 160:118–127

    Article  PubMed  Google Scholar 

  • Raison CL, Lin JM, Reeves WC et al (2009) Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain Behav Immun 23:327–337

    Article  CAS  PubMed  Google Scholar 

  • Reinikainen KJ, Riekkinen PJ, Halonen T, Laakso M (1987) Decreased muscarinic receptor binding in cerebral cortex and hippocampus in Alzheimer’s disease. Life Sci 41:453–461

    Article  CAS  PubMed  Google Scholar 

  • Rinne JO, Laakso K, Lönnberg P et al (1985) Brain muscarinic receptors in senile dementia. Brain Res 336:19–25

    Article  CAS  PubMed  Google Scholar 

  • Selkoe DJ (1990) Deciphering Alzheimer’s disease: the amyloid precursor protein yields new clues. Science 248:1058–1060

    Article  CAS  PubMed  Google Scholar 

  • Snyder SH, Chang KJ, Kuhar MJ et al (1975) Biochemical identification of the mammalian muscarinic cholinergic receptor. Feder Proc 34:1915–1921

    CAS  Google Scholar 

  • Suhara T, Inoue O, Kobayashi K et al (1993) Age-related changes inhuman muscarinic acetylcholine receptors measured by positron emission tomography. Neurosci Lett 149:225–228

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Murakami M, Miura S et al (1997) Radiosynthesis and biodistribution of [11C]3NMPB enantiomers in rats for studying muscarinic cholinergic receptors using PET. J Labelled Compd Radiopharm 40:613–615

    Google Scholar 

  • Tanaka S, Kuratsune H, Hidaka Y et al (2003) Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. Int J Mol Med 12:225–230

    CAS  PubMed  Google Scholar 

  • Tejani-Butt SM, Luthin GR, Wolfe BB et al (1990) N-substituted derivatives of 4-piperidinyl benzilate: affinities for brain muscarinic acetylcholine receptors. Life Sci 47:841–848

    Article  CAS  PubMed  Google Scholar 

  • Terry AV Jr, Buccafusco JJ (2003) The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 306:821–827

    Article  CAS  PubMed  Google Scholar 

  • Tsukada H, Harada N, Nishiyama S et al (2000a) Ketamine decreased striatal [11C]raclopride binding with no alteration in static dopamine concentrations in the striatal extracellular fluid in the monkey brain: multi-parametric PET studies combined with microdialysis analysis. Synapse 37:95–103

    Article  CAS  PubMed  Google Scholar 

  • Tsukada H, Harada N, Nishiyama S et al (2000b) Cholinergic neuronal modulation alters dopamine D2 receptor availability in vivo by regulating receptor affinity induced by facilitated synaptic dopamine turnover: PET studies with microdialysis in the conscious monkey brain. J Neurosci 20:7067–7073

    CAS  PubMed  Google Scholar 

  • Tsukada H, Sato K, Kakiuchi T et al (2000c) Age-related impairment of coupling mechanism between neuronal activation and functional cerebral blood flow response was restored by cholinesterase inhibition: PET study with microdialysis in the awake monkey brain. Brain Res 857:158–164

    Article  CAS  PubMed  Google Scholar 

  • Tsukada H, Kakiuchi T, Nishiyama S et al (2001a) Age differences in muscarinic cholinergic receptors assayed with (+)N-[11C]methyl-3-piperidyl benzilate in the brains of conscious monkeys. Synapse 41:248–257

    Article  CAS  PubMed  Google Scholar 

  • Tsukada H, Nishiyama S, Kakiuchi T et al (2001b) Ketamine alters the availability of striatal dopamine transporter as measured by [11C]β-CFT and [11C]β-CIT-FE in the monkey brain. Synapse 42:273–280

    Article  CAS  PubMed  Google Scholar 

  • Tsukada H, Takahashi K, Miura S et al (2001c) 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. Synapse 39:182–192

    Article  CAS  PubMed  Google Scholar 

  • Tsukada H, Nishiyama S, Fukumoto D et al (2004) Effects of acute acetylcholinesterase inhibition on the cerebral cholinergic neuronal system and cognitive function: functional imaging of the conscious monkey brain using animal PET in combination with microdialysis. Synapse 52:1–10

    Article  CAS  PubMed  Google Scholar 

  • Tsukada H, Ohba H, Nishiyama S, Kakiuchi T (2011) Differential effects of stress on [11C]raclopride and [11C]MNPA binding to striatal D2/D3 dopamine receptors: a PET study in conscious monkeys. Synapse 64:84–89

    Article  Google Scholar 

  • Vora MM, Finn RD, Boothe TE (1983) [N-methyl-11C]scopolamine: synthesis and distribution in rat brain. J Labelled Compd Radiopharm 20:1229–1234

    Article  CAS  Google Scholar 

  • Watanabe M, Okada H, Shimizu K et al (1997) A high resolution animal PET scanner using compact PS-PMT detectors. IEEE Trans Nucl Sci 44:1277–1282

    Article  CAS  Google Scholar 

  • Yamamoto S, Ohba H, Nishiyama S et al (2010) Validation of reference tissue model of PET ligand [11C](+)3-MPB for the muscarinic cholinergic receptor in the living brain of conscious monkey. Synapse 65:548–551

    Article  Google Scholar 

  • Yamamoto S, Maruyama S, Ito Y et al (2011a) Effect of oxybutynin and imidafenacin on central muscarinic receptor occupancy and cognitive function: a monkey PET study with [11C](+)3-MPB. Neuroimage 58:1–9

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto S, Nishiyama S, Kawamata M et al (2011b) Muscarinic receptor occupancy and cognitive impairment: a PET study with [11C](+)3-MPB and scopolamine in conscious monkeys. Neuropsychopharmacology 36:1455–1465

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto S, Ouchi Y, Nakatsuka D et al (2012) Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor. PLoS ONE 7:e51515

    Google Scholar 

  • Yokoyama C, Tsukada H, Watanabe Y, Onoe H (2005) A dynamic shift of neural network activity before and after learning-set formation. Cereb Cortex 15:796–801

    Article  PubMed  Google Scholar 

  • Yoshida T, Kuwabara Y, Ichiya Y et al (1998) Cerebral muscarinic acetylcholinergic receptor measurement in Alzheimer’s disease patient on 11C-methyl-4-piperidyl benzilate – comparison with cerebral blood flow and cerebral glucose metabolism. Ann Nucl Med 12:35–42

    Article  CAS  PubMed  Google Scholar 

  • Zubieta JK, Koeppe RA, Mulholland GK et al (1998) Quantification of muscarinic cholinergic receptors with [11C]NMPB and positron emission tomography: method development and differentiation of tracer delivery from receptor binding. J Cereb Blood Flow Metab 18:619–631

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Central Research Laboratory, Hamamatsu Photonics K.K., 5000 Hirakuchi, Hamakita, Hamamatsu, Shizuoka, 434-8601, Japan

    Hideo Tsukada

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  1. Hideo Tsukada
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Correspondence to Hideo Tsukada .

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Editors and Affiliations

  1. Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands

    Rudi A.J.O. Dierckx

  2. Faculty of Electrical Engineering and Information Technology, University of Applied Sciences Offenburg, Offenburg, Germany

    Andreas Otte

  3. Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands

    Erik F.J. de Vries

  4. Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Groningen, The Netherlands

    Aren van Waarde

  5. Molecular Neurobiology, Universtiy of Groningen, Groningen, The Netherlands

    Paul G.M. Luiten

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Tsukada, H. (2014). PET Imaging of Muscarinic Receptors. In: Dierckx, R., Otte, A., de Vries, E., van Waarde, A., Luiten, P. (eds) PET and SPECT of Neurobiological Systems. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-42014-6_16

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  • DOI: https://doi.org/10.1007/978-3-642-42014-6_16

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  • Online ISBN: 978-3-642-42014-6

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