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Molecular Imaging and Biology
Published in: Molecular Imaging and Biology 3/2019

01-06-2019 | Research Article

Characterization of [11C]PXT012253 as a PET Radioligand for mGlu4 Allosteric Modulators in Nonhuman Primates

Authors: Akihiro Takano, Sangram Nag, Zhisheng Jia, Mahabuba Jahan, Anton Forsberg, Ryosuke Arakawa, Per Grybäck, Guillaume Duvey, Christer Halldin, Delphine Charvin

Published in: Molecular Imaging and Biology | Issue 3/2019

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Abstract

Purpose

Modulation of presynaptic metabotropic glutamate receptor 4 (mGlu4) by an allosteric ligand has been proposed as a promising therapeutic target in Parkinson’s disease and levodopa-induced dyskinesia. A positron emission tomography (PET) ligand for an allosteric site of mGlu4 may provide evidence that a clinical drug candidate reaches and binds the target. A carbon-11-labeled PET radioligand binding an allosteric site of mGlu4, [11C]PXT012253, has been recently developed. Here, we describe the detailed characterization of this novel radiolabeled mGlu4 ligand in nonhuman primates.

Procedures

[11C]PXT012253 binding in the brain of cynomolgus monkeys, under the baseline and blocking conditions with the structurally different mGlu4 allosteric ligand PXT002331, currently in clinical trials for Parkinson’s disease, was quantified with compartment and graphical modeling approaches using a radiometabolite-corrected plasma input function. Whole-body biodistribution of [11C]PXT012253 was then assessed using PET/x-ray computed tomography to estimate the human effective doses of [11C]PXT012253 for further clinical studies.

Results

[11C]PXT012253 displayed binding in mGlu4-expressing regions in the brain of cynomolgus monkeys. Brain regional time-activity curves of [11C]PXT012253 were well described in the two-tissue compartment model (2TC). Total distribution volume was stably estimated using Logan plot and multilinear analysis (MA1) although 2TC showed unstable values in some cases. Competition with PXT002331 showed high specific binding in the total distribution volume. Whole-body PET showed high accumulation of [11C]PXT012253 in the liver, kidney, heart, and brain in the initial phase. The radioligand was excreted through both the gastrointestinal and the urinary tracts. Effective dose of [11C]PXT012253 was estimated to be 0.0042 mSv/MBq.

Conclusions

[11C]PXT012253 was shown to be a promising PET radioligand for mGlu4 allosteric modulators in the monkey brain. MA1 would be the choice of quantitative method. Further development of [11C]PXT012253 in human subjects is warranted.
Appendix
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Literature
1.
Zanotti-Fregonara P, Xu R, Zoghbi SS, Liow JS, Fujita M, Veronese M, Gladding RL, Rallis-Frutos D, Hong J, Pike VW, Innis RB (2016) The PET radioligand 18F-FIMX images and quantifies metabotropic glutamate receptor 1 in proportion to the regional density of its gene transcript in human brain. J Nucl Med 57:242–247CrossRefPubMed
2.
Wong DF, Waterhouse R, Kuwabara H, Kim J, Brasic JR, Chamroonrat W, Stabins M, Holt DP, Dannals RF, Hamill TG, Mozley PD (2013) 18F-FPEB, a PET radiopharmaceutical for quantifying metabotropic glutamate 5 receptors: a first-in-human study of radiochemical safety, biokinetics, and radiation dosimetry. J Nucl Med 54:388–396CrossRefPubMed
3.
Kimura Y, Siméon FG, Zoghbi SS, Zhang Y, Hatazawa J, Pike VW, Innis RB, Fujita M (2012) Quantification of metabotropic glutamate subtype 5 receptors in the brain by an equilibrium method using 18F-SP203. Neuroimage 59:2124–2130CrossRefPubMed
4.
Lohith TG, Tsujikawa T, Siméon FG, Veronese M, Zoghbi SS, Lyoo CH, Kimura Y, Morse CL, Pike VW, Fujita M, Innis RB (2017) Comparison of two PET radioligands, [11C]FPEB and [11C]SP203, for quantification of metabotropic glutamate receptor 5 in human brain. J Cereb Blood Flow Metab 37:2458–2470CrossRefPubMed
5.
Esterlis I, DellaGioia N, Pietrzak RH et al (2017) Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression. Mol Psychiatry 23:824–832CrossRefPubMedPubMedCentral
6.
DeLorenzo C, Gallezot JD, Gardus J, Yang J, Planeta B, Nabulsi N, Ogden RT, Labaree DC, Huang YH, Mann JJ, Gasparini F, Lin X, Javitch JA, Parsey RV, Carson RE, Esterlis I (2017) In vivo variation in same-day estimates of metabotropic glutamate receptor subtype 5 binding using [11C]ABP688 and [18F]FPEB. J Cereb Blood Flow Metab 37:2716–2727CrossRefPubMed
7.
Charvin D (2018) mGlu4 allosteric modulation for treating Parkinson’s disease. Neuropharmacology 135:308–315CrossRefPubMed
8.
Sebastianutto I, Cenci MA (2018) mGlu receptors in the treatment of Parkinson’s disease and L-DOPA-induced dyskinesia. Curr Opin Pharmacol 38:81–89CrossRefPubMed
9.
Marino MJ, Williams DL Jr, O’Brien JA et al (2003) Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson’s disease treatment. Proc Natl Acad Sci U S A 100:13668–13673CrossRefPubMedPubMedCentral
10.
Charvin D, Di Paolo T, Bezard E, et al. (2018) A mGluR4 positive allosteric modulator alleviates parkinsonism in primates. in press
11.
Kil KE, Poutiainen P, Zhang Z, Zhu A, Kuruppu D, Prabhakar S, Choi JK, Tannous BA, Brownell AL (2016) Synthesis and evaluation of N-(methylthiophenyl)picolinamide derivatives as PET radioligands for metabotropic glutamate receptor subtype 4. Bioorg Med Chem Lett 26:133–139CrossRefPubMed
12.
Kil K, Zhang Z, Zhu A et al (2014) Radiosyntheses and preclinical evaluation of two N-(3-[11C]methylthiophenyl)-2-picolinamide ([11C]ML128) derivatives as radiotracers for mGlu4. J Nucl Med May 55(supplement 1):1169
13.
Andersson J, Truong P, Halldin C (2009) In-target produced [11C]methane: increased specific radioactivity. Appl Radiat Isot 67:106–110CrossRefPubMed
14.
Varrone A, Sjöholm N, Eriksson L, Gulyás B, Halldin C, Farde L (2009) Advancement in PET quantification using 3D-OP-OSEM point spread function reconstruction with the HRRT. Eur J Nucl Med Mol Imaging 36:1639–1650CrossRefPubMed
15.
Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, MacGregor RR, Hitzemann R, Bendriem B, Gatley SJ, Christman DR (1990) Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 10:740–747CrossRefPubMed
16.
Ichise M, Toyama H, Innis RB, Carson RE (2002) Strategies to improve neuroreceptor parameter estimation by linear regression analysis. J Cereb Blood Flow Metab 22:1271–1281CrossRefPubMed
17.
Akaike H (1976) An information criterion (AIC). Math Sci 14:5–9
18.
Lassen NA, Bartenstein PA, Lammertsma AA, Prevett MC, Turton DR, Luthra SK, Osman S, Bloomfield PM, Jones T, Patsalos PN, O'Connell MT, Duncan JS, Andersen JV (1995) Benzodiazepine receptor quantification in vivo in humans using [11C]flumazenil and PET: application of the steady-state principle. J Cereb Blood Flow Metab 15:152–165CrossRefPubMed
19.
Stabin MG, Sparks RB, Crowe E (2005) OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 46:1023–1027PubMed
20.
Makoff A, Lelchuk R, Oxer M, Harrington K, Emson P (1996) Molecular characterization and localization of human metabotropic glutamate receptor type 4. Brain Res Mol Brain Res 37:239–248CrossRefPubMed
21.
Kil KE, Poutiainen P, Zhang Z, Zhu A, Choi JK, Jokivarsi K, Brownell AL (2014) Radiosynthesis and evaluation of an 18F-labeled positron emission tomography (PET) radioligand for metabotropic glutamate receptor subtype 4 (mGlu4). J Med Chem 57:9130–9138CrossRefPubMedPubMedCentral
22.
23.
Arakawa R, Farde L, Matsumoto J, Kanegawa N, Yakushev I, Yang KC, Takano A (2018) Potential effect of prolonged sevoflurane anesthesia on the kinetics of [11C]raclopride in non-human primates. Mol Imaging Biol 20:183–187CrossRefPubMed
24.
Zanotti-Fregonara P, Innis RB (2012) Suggested pathway to assess radiation safety of 11C-labeled PET tracers for first-in-human studies. Eur J Nucl Med Mol Imaging 39:544–547CrossRefPubMed
Metadata
Title
Characterization of [11C]PXT012253 as a PET Radioligand for mGlu4 Allosteric Modulators in Nonhuman Primates
Authors
Akihiro Takano
Sangram Nag
Zhisheng Jia
Mahabuba Jahan
Anton Forsberg
Ryosuke Arakawa
Per Grybäck
Guillaume Duvey
Christer Halldin
Delphine Charvin
Publication date
01-06-2019
Publisher
Springer International Publishing
Published in
Molecular Imaging and Biology / Issue 3/2019
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-018-1257-0

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