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Brain Imaging of the Glutamatergic System: First-in-man Evaluation of a Novel 18F-PET Radioligand Targeting mGlu5 in Caucasian and Asian subjects and the Development of a PET Ligand for Imaging Glutamatergic GluN2A Receptor Subtype

English title Brain Imaging of the Glutamatergic System: First-in-man Evaluation of a Novel 18F-PET Radioligand Targeting mGlu5 in Caucasian and Asian subjects and the Development of a PET Ligand for Imaging Glutamatergic GluN2A Receptor Subtype
Applicant Ametamey Simon M.
Number 162196
Funding scheme South Korea
Research institution Zentrum für Radiopharmazeutische Wissenschaften ETH, PSI, USZ ETH Hönggerberg
Institution of higher education ETH Zurich - ETHZ
Main discipline Neurology, Psychiatry
Start/End 01.03.2016 - 31.08.2020
Approved amount 250'000.00
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Keywords (6)

metabotropic glutamate receptor subtype 5; GluN2A glutamatergic receptor subtype; clinical phase 1 study; 18F-PSS232; PET imaging; Caucasian and Asian healthy volunteers

Lay Summary (German)

Lead
Das glutamaterge System spielt eine wichtige Rolle bei kognitiven Vorgängen wie Lernen und Gedächtnis, aber auch bei akuter und chronischer Schädigung von Neuronen nach einem Schlaganfall, einer Kopfverletzung oder während der Entwicklung neurodegenerativer Erkrankungen. In den letzten Jahren haben intensive Untersuchungen gezeigt, dass der metabotrope Glutamatrezeptor vom Subtyp 5 (mGlu5) und der NMDA (N-Methyl-D-aspartat)-Rezeptor an der Entsteheung von zahlreichen Erkrankungen wie Morbus Parkinson, Morbus Alzheimer, Depression und Epilepsie beteiligt sind. Der NMDA-Rezeptor gehört zur Klasse der ionotropen Glutamat-Rezeptoren und ist aus vier Untereinheiten aufgebaut. Nicht invasive bildgebende Verfahren wie Positronen Emissions Tomographie (PET) ermöglichen die Darstellung und die Analyse von Hirnrezeptoren.
Lay summary
Dieses Projekt ist der Bildgebung von mGlu5 und NMDA-Rezeptoren mit GluN2A-Untereinheit gewidmet. Zunächst soll die Darstellung von mGlu5 in gesunden Probanden caucasischen und asiatischen Ursprungs mit dem kürzlich veröffentlichen Fluor-18 markierten PET-Liganden untersucht werden um herauszufinden, ob es Unterschiede in der Hirnaufnahme gibt. Weiterhin sollen neue PET-Liganden für die Darstellung der GluN2A-Untereinheit entwickelt werden. In Vorarbeiten haben wir eine neue Substanzklasse für die GluN2A-Untereinheit entwicklet jedoch haben die Substanzen einen Nachteil, dass sie nicht hirngängig sind. Auf Grund ihrer hohen GluN2A-Affinität sollen diese Substanzen als Leitverbindung für dieses Projekt dienen. Um einen hirngängige PET-Liganden zu erhalten, sollen verschiedene Struktureinheiten in unterschiedlichen Positionen der GluN2A-Liganden eingeführt werden. Nach der Radiosynthese sollen die chemische und metabolische Stabilität, Plasmaprotein-Bindung und Passage der Blut-Hirn-Schranke der neuen Verbindungen untersucht werden. Die Optimierung der unterschiedlichen Eigenschaften der Liganden erfordert eine iterative Vorgehensweise. Nach Auswahl der besten Substanz sollen die biologischen Eigenschaften der PET-Liganden evaluiert werden.
Direct link to Lay Summary Last update: 10.11.2015

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Evaluation of 5H-thiazolo[3,2-alpha]pyrimidin-5-ones as potential GluN2A PET tracers
He Yingfang et al. (2020), Evaluation of 5H-thiazolo[3,2-alpha]pyrimidin-5-ones as potential GluN2A PET tracers, in ChemMedChem, 15, 1-15.
A first-in man study of 18F-PSS232, fluorinated ABP688 derivative for imaging metabotropic glutamate receptor subtype 5
Warnock Geoffrey et al., A first-in man study of 18F-PSS232, fluorinated ABP688 derivative for imaging metabotropic glutamate receptor subtype 5, in European Journal of Nuclear Medicine and Molecular Imaging.
Synthesis and Biological Evaluation of Quinoxaline Derivatives for PET Imaging of the NMDA Receptor
Sephton Milicevic Selena et al., Synthesis and Biological Evaluation of Quinoxaline Derivatives for PET Imaging of the NMDA Receptor, in Helvetica Chimica Acta.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Kim Q. Do Cuénod Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Novartis Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Joong-Hyun Chun, University of Yonsei Korean Republic (South Korea) (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Dr. Yves Auberson/Novartis Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Philipp Kaufmann Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Radiopharmacy Day Individual talk Development of fluorine-18 based PET ligand for imaging glutamatergic GluN2A receptor subtype 09.11.2018 Villigen, Switzerland He Yingfang; Ametamey Simon M.; Gruber Stefan;
Trimester Report Individual talk GluN2A Project 22.02.2018 Zürich, Switzerland He Yingfang; Ametamey Simon M.; Gruber Stefan;
Seminartag am PSI, Villigen Individual talk Development of a fluorine-18 based PET ligand for imaging glutamatergic GluN2A receptor subtype 02.09.2016 Villigen, Switzerland Gruber Stefan; Ametamey Simon M.;


Abstract

Summary of the research plan Background: The impact of mental disorders such as depression and other affective disorders on the mortality of patients implies an unmet need for action in neuroscience. The glutamatergic system consisting of ionotropic ligand-gated cationic channels and metabotropic glutamate receptors, which are G-protein-coupled receptor, has been implicated in several brain disorders. Specifically, the metabotropic glutamate receptor subtype 5 (mGlu5) and the N-methyl-D-aspartate receptor (NMDAR) have emerged as attractive therapeutic targets because of their implication in the pathophysiology of major psychiatric and neurological disorders such as depression, addiction, Parkinson`s disease, Fragile X syndrome and inflammatory pain. Molecular imaging of the human glutamatergic system predominantly using PET studies would help to understand the neurochemical defects within the brain using potential glutamatergic receptor PET ligands.Status of Own Research:The research group at the Center for Radiopharmaceutical Sciences of ETH Zurich reported on a new mGlu5 PET radiotracer, 3-(6-Methyl-pyridin-2-yl-ethynyl)-cyclohex-2-enone-O-[11C]methyl-oxime ([11C]ABP688), which to date, is the most widely clinically applied PET radiotracer for imaging mGlu5 in humans. [11C]ABP688, however, has a limited clinical utility because of the short physical half-life of carbon-11 (20 min). The ETH Zurich group has recently, through strenuous efforts, identified an excellent fluorine-18 (T1/2 = 110 min) labeled compound designated [18F]PSS232, which shows excellent in vitro and in vivo properties including high selectivity and specificity for mGlu5 in a preclinical setting. Binding affinities to rat and human mGlu5 were 1.3 and 1.1 nM, respectively. PET studies in rats of 18F-PSS232 showed specific accumulation in mGlu5 rich regions. The PET imaging studies were highly reproducible and showed less than 7% between-animal variability in agreement with test-retest experiment.These impressive results strongly support the further evaluation of [18F]PSS232 in a first proof-of-concept study in humans. First PET imaging studies obtained recently in Zurich in three healthy volunteers show promising results. With regard to glutamatergic NMDAR, the Zurich group has recently identified through structure-activity relationships (SARs) novel quinoxalinedione derivatives, which show high nanomolar binding affinity and selectivity to the GluN2A subunit on the glutamate binding site of the NMDAR. We seek now to use a prodrug approach to develop these quinoxalinedione derivatives as PET imaging agents for the GluN2A subunit of the NMDAR. Yonsei University Health System (Severance Hospital) is one of the leading hospitals in South Korea which has a daily patient volume of approx. 11,000. In addition to excellent patient care and proven history of many successful clinical studies, the Yonsei group showcased the first successful human evaluation of integrin binding PET tracer with 18F-RGD-K5 in breast cancer patient through the eIND (exploratory IND) study. Goals of the Project: With this Swiss-South Korea JRP, we propose to perform a pan-continental two-center clinical study with the above mentioned novel 18F-PET tracer targeting the mGlu5. The first goal is to establish a GMP (Good Manufacturing Practice) production of [18F]PSS232, developed by the Zurich group, in South Korea and to perform a first proof-of-concept studies in 10 healthy volunteers of Asian origin in South Korea (Yonsei University). A comparative evaluation of the human data obtained from Caucasian healthy volunteers at ETH Zurich (Center for Radiopharmaceutical Sciences) and South Korean subjects will be carried out to validate the potential of the new ligand in two different ethinicities. The second goal (subproject B) involves the joint development of a highly specific and selective PET ligand for imaging GluN2A subunit of the glutamatergic NMDAR.Expected Value of the Proposed Study:The successful accomplishment of the goals of this project will provide unlimited access of [18F]PSS232 through satellite distributions by Yonsei University (South Korean partner) and ETH-Zurich (Swiss partner) to research groups within Switzerland and South Korea which have a strong desire to perform mGlu5 PET imaging studies but have limited or no radiochemistry facilities. Performing the PET studies in two different centers will also increase the reliability of the PET data and also establish whether or not differences in ethnicities exist between people of Asian and European origin. NMDAR and mGlu5 share a structural and functional link therefore accessing other glutamatergic NMDA receptors such as GluN2A subunit of the NMDAR in addition to mGlu5 will feature research on mental diseases and improve our understanding of the pathophysiologies of these brain disorders. There are currently no PET radioligands for imaging the NMDAR in humans. As such, a successful outcome of this project will change the scientific landscape on neuropsychiatric drug development, and pave the way for a better management of patients suffering thereof. Young scientists will be trained in areas such as radiopharmaceutical chemistry and the GMP production of radiopharmaceuticals. Both sites in Switzerland and South Korea will profit from the capabilities and expertise of each other.
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