Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Molecular Imaging and Biology
Published in: Molecular Imaging and Biology 4/2019

Open Access 01-08-2019 | Research Article

Evaluation of the Novel PET Tracer [11C]HACH242 for Imaging the GluN2B NMDA Receptor in Non-Human Primates

Authors: Jasper van der Aart, Maqsood Yaqub, Esther J. M. Kooijman, Jaco Bakker, Jan A. M. Langermans, Robert C. Schuit, Mark B. M. Hofman, Johannes A. M. Christiaans, Adriaan A. Lammertsma, Albert D. Windhorst, Bart N. M. van Berckel

Published in: Molecular Imaging and Biology | Issue 4/2019

Login to get access

Abstract

Purpose

There are currently no positron emission tomography (PET) radiotracers for the GluN2B (NR2B) binding sites of brain N-methyl-d-aspartate (NMDA) receptors. In rats, the GluN2B antagonist Ro25-6981 reduced the binding of N-((5-(4-fluoro-2-[11C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamin ([11C]HACH242). This paper reports the evaluation of [11C]HACH242 PET in non-human primates at baseline and following administration of the GluN2B negative allosteric modulator radiprodil.

Procedures

Eight 90-min dynamic [11C]HACH242 PET scans were acquired in three male anaesthetised rhesus monkeys, including a retest session of subject 1, at baseline and 10 min after intravenous 10 mg/kg radiprodil. Standardised uptake values (SUV) were calculated for 9 brain regions. Arterial blood samples were taken at six timepoints to characterise pharmacokinetics in blood and plasma. Reliable input functions for kinetic modelling could not be generated due to variability in the whole-blood radioactivity measurements.

Results

[11C]HACH242 entered the brain and displayed fairly uniform uptake. The mean (± standard deviation, SD) Tmax was 17 ± 7 min in baseline scans and 24 ± 15 min in radiprodil scans. The rate of radioligand metabolism in plasma (primarily to polar metabolites) was high, with mean parent fractions of 26 ± 10 % at 20 min and 8 ± 5 % at 85 min. Radiprodil increased [11C]HACH242 whole-brain SUV in the last PET frame by 25 %, 1 %, 3 and 17 % for subjects 1, 2, 3 and retest of subject 1, respectively. The mean brain to plasma ratio was 5.4 ± 2.6, and increased by 39 to 110 % in the radiprodil condition, partly due to lower parent plasma radioactivity of −11 to −56 %.

Conclusions

The present results show that [11C]HACH242 has a suitable kinetic profile in the brain and low accumulation of lipophilic radiometabolites. Radiprodil did not consistently change [11C]HACH242 brain uptake. These findings may be explained by variations in cerebral blood flow, a low fraction of specifically bound tracer, or interactions with endogenous NMDA receptor ligands at the binding site. Further experiments of ligand interactions are necessary to facilitate the development of radiotracers for in vivo imaging of the ionotropic NMDA receptor.
Literature
1.
Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14:383–400CrossRef
2.
Mony L, Krzaczkowski L, Leonetti M, le Goff A, Alarcon K, Neyton J, Bertrand HO, Acher F, Paoletti P (2009) Structural basis of NR2B-selective antagonist recognition by N-methyl-D-aspartate receptors. Mol Pharmacol 75:60–74CrossRefPubMed
3.
Loftis JM, Janowsky A (2003) The N-methyl-d-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications. Pharmacol Ther 97:55–85CrossRefPubMed
4.
Laurie DJ, Bartke I, Schoepfer R, Naujoks K, Seeburg PH (1997) Regional, developmental and interspecies expression of the four NMDAR2 subunits, examined using monoclonal antibodies. Brain Res Mol Brain Res 51:23–32CrossRef
5.
Sobrio F, Gilbert G, Perrio C, Barre L, Debruyne D (2010) PET and SPECT imaging of the NMDA receptor system: an overview of radiotracer development. Mini Rev Med Chem 10:870–886CrossRefPubMed
6.
Klein PJ, Christiaans JAM, Metaxas A, Schuit RC, Lammertsma AA, van Berckel BNM, Windhorst AD (2015) Synthesis, structure activity relationship, radiolabeling and preclinical evaluation of high affinity ligands for the ion channel of the N-methyl-d-aspartate receptor as potential imaging probes for positron emission tomography. Bioorg Med Chem 23:1189–1206CrossRefPubMed
7.
Fuchigami T, Nakayama M, Yoshida S (2015) Development of PET and SPECT probes for glutamate receptors. Sci World J 2015:1–19CrossRef
8.
Labas R, Gilbert G, Nicole O, Dhilly M, Abbas A, Tirel O, Buisson A, Henry J, Barré L, Debruyne D, Sobrio F (2011) Synthesis, evaluation and metabolic studies of radiotracers containing a 4-(4-[18F]-fluorobenzyl)piperidin-1-yl moiety for the PET imaging of NR2B NMDA receptors. Eur J Med Chem 46:2295–2309CrossRefPubMed
9.
van der Aart J, Golla SSV, van der Pluijm M, Schwarte LA, Schuit RC, Klein PJ, Metaxas A, Windhorst AD, Boellaard R, Lammertsma AA, van Berckel BNM (2018) First in human evaluation of [18F]PK-209, a PET ligand for the ion channel binding site of NMDA receptors. EJNMMI Res Res 8:69CrossRef
10.
Roger G, Dollé F, De Bruin B, Liu X, Besret L, Bramoullé Y, Coulon C, Ottaviani M, Bottlaender M, Valette H, Kassiou M (2004) Radiosynthesis and pharmacological evaluation of [11C]EMD-95885: a high affinity ligand for NR2B-containing NMDA receptors. Bioorg Med Chem 12:3229–3237CrossRefPubMed
11.
Brown DG, Maier DL, Sylvester MA, Hoerter TN, Menhaji-Klotz E, Lasota CC, Hirata LT, Wilkins DE, Scott CW, Trivedi S, Chen T, McCarthy DJ, Maciag CM, Sutton EJ, Cumberledge J, Mathisen D, Roberts J, Gupta A, Liu F, Elmore CS, Alhambra C, Krumrine JR, Wang X, Ciaccio PJ, Wood MW, Campbell JB, Johansson MJ, Xia J, Wen X, Jiang J, Wang X, Peng Z, Hu T, Wang J (2011) 2,6-Disubstituted pyrazines and related analogs as NR2B site antagonists of the NMDA receptor with anti-depressant activity. Bioorg Med Chem Lett 21:3399–3403CrossRefPubMed
12.
Christiaans JAM, Klein PJ, Metaxas A, Kooijman EJM, Schuit RC, Leysen JE, Lammertsma AA, van Berckel BNM, Windhorst AD (2014) Synthesis and preclinical evaluation of carbon-11 labelled N-((5-(4-fluoro-2-[11C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamine as a PET tracer for NR2B subunit-containing NMDA receptors. Nucl Med Biol 41:670–680CrossRefPubMed
13.
Toyohara J, Sakata M, Ishiwata K (2012) Re-evaluation of in vivo selectivity of [11C]SA4503 to σ(1) receptors in the brain: contributions of emopamil binding protein. Nucl Med Biol 39:1049–1052CrossRefPubMed
14.
Bradford AM (2006) Molecular pharmacology of a novel NR2B-selective NMDA receptor antagonist. Doctoral thesis. In: Durham University
15.
Weatherall D, Goodfellow P, Harris J, Hinde R, Johnson L, Morris R, Ross N, Skehel J, Tickell C (2006) The use of non-human primates in research. The Royal Society, London
16.
Rohlfing T, Kroenke CD, Sullivan EV, Dubach MF, Bowden DM, Grant KA, Pfefferbaum A (2012) The INIA19 template and NeuroMaps atlas for primate brain image parcellation and spatial normalization. Front Neuroinform 6:27CrossRefPubMedPubMedCentral
17.
Golla SSV, Klein PJ, Bakker J, Schuit RC, Christiaans JAM, van Geest L, Kooijman EJM, Oropeza-Seguias GM, Langermans JAM, Leysen JE, Boellaard R, Windhorst AD, van Berckel BNM, Metaxas A (2015) Preclinical evaluation of [18F]PK-209, a new PET ligand for imaging the ion-channel site of NMDA receptors. Nucl Med Biol 42:205–212CrossRefPubMed
18.
Bai L, Hof PR, Standaert DG, Xing Y, Nelson SE, Young AB, Magnusson KR (2004) Changes in the expression of the NR2B subunit during aging in macaque monkeys. Neurobiol Aging 25:201–208CrossRefPubMed
19.
Charton JP, Herkert M, Becker CM, Schröder H (1999) Cellular and subcellular localization of the 2B-subunit of the NMDA receptor in the adult rat telencephalon. Brain Res 816:609–617CrossRefPubMed
20.
Kitaichi K, Chabot JG, Moebius FF, Flandorfer A, Glossmann H, Quirion R (2000) Expression of the purported sigma(1) receptor in the mammalian brain and its possible relevance in deficits induced by antagonism of the NMDA receptor complex as revealed using an antisense strategy. J Chem Neuroanat 20:375–387CrossRefPubMed
21.
Krämer SD, Betzel T, Mu L, Haider A, Herde AM, Boninsegni AK, Keller C, Szermerski M, Schibli R, Wünsch B, Ametamey SM (2018) Evaluation of [11C]Me-NB1 as a potential PET radioligand for measuring GluN2B-containing NMDA receptors, drug occupancy and receptor crosstalk. J Nucl Med 59:698–703CrossRefPubMed
22.
Başkaya MK, Rao AM, Donaldson D, Prasad MR, Dempsey RJ (1997) Protective effects of ifenprodil on ischemic injury size, blood-brain barrier breakdown, and edema formation in focal cerebral ischemia. Neurosurgery 40:364–370CrossRefPubMed
23.
Kastner SBR, Wapf P, Feige K, Demuth D, Bettschart- Wolfensberger R, Akens MK, Huhtinen M (2003) Pharmacokinetics and sedative effects of intramuscular medetomidine in domestic sheep. J Vet Pharmacol Ther 26:271–276CrossRefPubMed
24.
Waelbers T, Peremans K, Vermeire S, Duchateau L, Dobbeleir A, Audenaert K, Polis I (2011) The effect of medetomidine on the regional cerebral blood flow in dogs measured using technetium-99m-ethyl cysteinate dimer SPECT. Res Vet Sci 91:138–143CrossRefPubMed
25.
Veselis RA, Reinsel RA, Beattie BJ, Mawlawi OR, Feshchenko VA, DiResta GR, Larson SM, Blasberg RG (1997) Midazolam changes cerebral blood flow in discrete brain regions: an H2 15O positron emission tomography study. Anesthesiology 87:1106–1117CrossRefPubMed
26.
van der Doef TF, Golla SSV, Klein PJ, Oropeza-Seguias GM, Schuit RC, Metaxas A, Jobse E, Schwarte LA, Windhorst AD, Lammertsma AA, van Berckel BNM, Boellaard R (2016) Quantification of the novel N-methyl-d-aspartate receptor ligand [11C]GMOM in man. J Cereb Blood Flow Metab 36:1111–1121CrossRefPubMed
27.
Schoenberger M, Schroeder FA, Placzek MS, Carter RL, Rosen BR, Hooker JM, Sander CY (2018) In vivo [18F]GE-179 brain signal does not show NMDA-specific modulation with drug challenges in rodents and nonhuman primates. ACS Chem Neurosci 9:298–305CrossRefPubMed
28.
Haradahira T, Maeda J, Okauchi T, Zhang MR, Hojo J, Kida T, Arai T, Yamamoto F, Sasaki S, Maeda M, Suzuki K, Suhara T (2002) Synthesis, in vitro and in vivo pharmacology of a C-11 labeled analog of CP-101,606, (+/−)threo-1-(4-hydroxyphenyl)-2-[4-hydroxy-4-(p-[11C]methoxyphenyl)piperidino]-1-propanol, as a PET tracer for NR2B subunit-containing NMDA receptors. Nucl Med Biol 29:517–525CrossRefPubMed
29.
Sasaki S, Kurosaki F, Haradahira T, Yamamoto F, Maeda J, Okauchi T, Suzuki K, Suhara T, Maeda M (2004) Synthesis of 11C-labelled bis(phenylalkyl)amines and their in vitro and in vivo binding properties in rodent and monkey brains. Biol Pharm Bull 27:531–537CrossRefPubMed
30.
Yuan H, Myers SJ, Wells G, Nicholson KL, Swanger SA, Lyuboslavsky P, Tahirovic YA, Menaldino DS, Ganesh T, Wilson LJ, Liotta DC, Snyder JP, Traynelis SF (2015) Context-dependent GluN2B-selective inhibitors of NMDA receptor function are neuroprotective with minimal side effects. Neuron 85:1305–1318CrossRefPubMedPubMedCentral
31.
Stroebel D, Buhl DL, Knafels JD, Chanda PK, Green M, Sciabola S, Mony L, Paoletti P, Pandit J (2016) A novel binding mode reveals two distinct classes of NMDA receptor GluN2B-selective antagonists. Mol Pharmacol 89:541–551CrossRefPubMedPubMedCentral
Metadata
Title
Evaluation of the Novel PET Tracer [11C]HACH242 for Imaging the GluN2B NMDA Receptor in Non-Human Primates
Authors
Jasper van der Aart
Maqsood Yaqub
Esther J. M. Kooijman
Jaco Bakker
Jan A. M. Langermans
Robert C. Schuit
Mark B. M. Hofman
Johannes A. M. Christiaans
Adriaan A. Lammertsma
Albert D. Windhorst
Bart N. M. van Berckel
Publication date
01-08-2019
Publisher
Springer International Publishing
Published in
Molecular Imaging and Biology / Issue 4/2019
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-018-1284-x

Other articles of this Issue 4/2019

Molecular Imaging and Biology 4/2019 Go to the issue

Brief Article

Correlation of Tumor Perfusion Between Carbon-13 Imaging with Hyperpolarized Pyruvate and Dynamic Susceptibility Contrast MRI in Pre-Clinical Model of Glioblastoma

Research Article

Development of a Non-invasive Assessment of Hypoxia and Neovascularization with Magnetic Resonance Imaging in Benign and Malignant Breast Tumors: Initial Results

Research Article

Adenine Nucleotide Translocase 2 as an Enzyme Related to [18F] FDG Accumulation in Various Cancers

Research Article

[18F]FE-OTS964: a Small Molecule Targeting TOPK for In Vivo PET Imaging in a Glioblastoma Xenograft Model

Research Article

Impact of Tumor Burden on Quantitative [68Ga] DOTATOC Biodistribution

Research Article

Prognostic Value of Early Evaluation of Left Ventricular Dyssynchrony After Myocardial Infarction