Synthesis and Biological Evaluation of Enantiomerically Pure ( R )- and ( S )-[ 18 F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA receptors.

Autor:	Korff M; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Chaudhary A; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Li Y; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Zhou X; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Zhao C; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Rong J; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Chen J; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Xiao Z; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Elghazawy NH; Institute of Pharmacy, Department of Medicinal Chemistry, Martin-Luther-University Halle-Wittenberg, W.-Langenbeck-Str. 4, 06120 Halle, Germany., Sippl W; Institute of Pharmacy, Department of Medicinal Chemistry, Martin-Luther-University Halle-Wittenberg, W.-Langenbeck-Str. 4, 06120 Halle, Germany., Davenport AT; Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA., Daunais JB; Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA., Wang L; Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China., Abate C; Dipartimento di Farmacia-Scienze Del Farmaco, Università Degli Studi di Bari ALDO MORO, Via Orabona 4, Bari 70125, Italy., Ahmed H; Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Institute of Pharmaceutical Sciences ETH, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland., Crowe R; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Liang SH; Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA 30322, USA., Ametamey SM; Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Institute of Pharmaceutical Sciences ETH, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland., Wünsch B; Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany., Haider A; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Jan 27. Date of Electronic Publication: 2023 Jan 27.
DOI:	10.21203/rs.3.rs-2516002/v1
Abstrakt:	GluN2B subunit-containing N -methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. As part of our PET ligand development program, we have recently reported on the preclinical evaluation of [ 18 F]OF-NB1 - a GluN2B PET ligand with promising attributes for potential clinical translation. However, the further development of [ 18 F]OF-NB1 is currently precluded by major limitations in the radiolabeling procedure. These limitations include the use of highly corrosive reactants and racemization during the radiosynthesis. As such, the aim of this study was to develop a synthetic approach that allows an enantiomerically pure radiosynthesis of ( R )-[ 18 F]OF-NB1 and ( S )-[ 18 F]OF-NB1, as well as to assess their in vitro and in vivo performance characteristics for imaging the GluN2B subunit-containing NMDA receptor in rodents. A two-step radiosynthesis involving radiofluorination of the boronic acid pinacol ester, followed by coupling to the 3-benzazepine core structure via reductive amination was employed. The new synthetic approach yielded enantiomerically pure ( R )-[ 18 F]OF-NB1 and ( S )-[ 18 F]OF-NB1, while concurrently circumventing the use of corrosive reactants. In vitro autoradiograms with mouse and rat brain sections revealed a higher selectivity of ( R )-[ 18 F]OF-NB1 over ( S )-[ 18 F]OFNB1 for GluN2B-rich brain regions. In concert with these observations, blockade studies with commercially available GluN2B antagonist, CP101606, showed a significant signal reduction, which was more pronounced for ( R )-[ 18 F]OF-NB1 than for ( S )-[ 18 F]OF-NB1. Conversely, blockade experiments with sigma2 ligand, FA10, did not result in a significant reduction of tracer binding for both enantiomers. PET imaging experiments with CD1 mice revealed a higher brain uptake and retention for ( R )-[ 18 F]OF-NB1, as assessed by visual inspection and volumes of distribution from Logan graphical analyses. In vivo blocking experiments with sigma2 ligand, FA10, did not result in a significant reduction of the brain signal for both enantiomers, thus corroborating the selectivity over sigma2 receptors. In conclusion, we have developed a novel synthetic approach that is suitable for upscale to human use and allows the enantiomerically pure radiosynthesis of ( R )-[ 18 F]OF-NB1 and ( S )-[ 18 F]OF-NB1. While both enantiomers were selective over sigma2 receptors in vitro and in vivo , ( R )-[ 18 F]OF-NB1 showed superior GluN2B subunit specificity by in vitro autoradiography and higher volumes of distribution in small animal PET studies. Competing Interests: Conflict of interest H.A, S.M.A and A.H. are co-founders of Nemosia AG and co-authors of the following patents: WO2020099537A1 and US2017224852A1.
Databáze:	MEDLINE
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