Preclinical In Vitro and In Vivo Characterization of Synaptic Vesicle 2A-Targeting Compounds Amenable to F-18 Labeling as Potential PET Radioligands for Imaging of Synapse Integrity.

Autor: Patel S; Codiak Biosciences, 500 Technology Square, 9th Floor, Cambridge, MA, 02139, USA. shil.patel@codiakbio.com., Knight A; Centre for Addiction and Mental Health, University of Toronto, 250 College Street, Toronto, ON, M5T 1R8, Canada., Krause S; Eisai Inc., 100 Tice Blvd, Woodcliff Lake, NJ, 07677, USA., Teceno T; Eisai Inc., 100 Tice Blvd, Woodcliff Lake, NJ, 07677, USA., Tresse C; Invicro, LLC, 27 Drydock Ave. 7th Floor West, Boston, MA, 02210, USA., Li S; PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 801 Howard Avenue, New Haven, CT, 06510, USA., Cai Z; PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 801 Howard Avenue, New Haven, CT, 06510, USA., Gouasmat A; Invicro, LLC, 27 Drydock Ave. 7th Floor West, Boston, MA, 02210, USA., Carroll VM; Invicro, LLC, 27 Drydock Ave. 7th Floor West, Boston, MA, 02210, USA., Barret O; Invicro, LLC, 27 Drydock Ave. 7th Floor West, Boston, MA, 02210, USA., Gottmukkala V; Invicro, LLC, 27 Drydock Ave. 7th Floor West, Boston, MA, 02210, USA., Zhang W; Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China., Xiang X; Department of Interventional Radiology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan Second Road, Yuexiu District, Guangzhou, 510080, China., Morley T; Invicro, LLC, 27 Drydock Ave. 7th Floor West, Boston, MA, 02210, USA., Huang Y; PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 801 Howard Avenue, New Haven, CT, 06510, USA., Passchier J; Invicro, LLC, 27 Drydock Ave. 7th Floor West, Boston, MA, 02210, USA.
Jazyk: angličtina
Zdroj: Molecular imaging and biology [Mol Imaging Biol] 2020 Aug; Vol. 22 (4), pp. 832-841.
DOI: 10.1007/s11307-019-01428-0
Abstrakt: Purpose: Current synaptic vesicle 2A (SV2A) positron emission tomography (PET) imaging agents include the nanomolar affinity probes [ 11 C]UCB-J and [ 18 F]UCB-H derived from the anti-epileptic drug levitaracetam (Keppra®). An industry-utilized "de-risking" approach was used to carry out initial pharmacological characterization and to assess potential next-generation candidates amenable to F-18 radiolabeling for preliminary evaluation.
Procedures: Radioligand binding methods were employed in mammalian brain homogenates to determine the SV2A affinity (K d ) and maximal binding capacity (B max ) of [ 3 H]UCB-J. Novel leads were then screened to identify compounds minimally with comparable binding affinities with UCB-J in order to select a F-18-labeled candidate for subsequent in vivo assessment in rat. In parallel, mammalian brain tissue section autoradiography was performed to assess specific SV2A distribution.
Results: [ 3 H]UCB-J bound with high affinity to a single population of sites in the rat brain (K d  = 2.6 ± 0.25 nM; B max  = 810 ± 25 fmol/mg protein) and control human cortex (K d  = 2.9 ± 0.54 nM; B max  = 10,000 ± 640 fmol/mg protein). Distribution of specific SV2A binding was shown to be homogeneous throughout the rodent brain and primarily in gray matter regions of rodent and human brain sections. Analog screening identified MNI-1038, MNI-1126/SDM-8, and SDM-2 as having comparable binding affinities with the currently available PET ligands. Subsequent [ 18 F]MNI-1126/[ 18 F]SDM-8 dynamic micro-PET imaging in rats revealed in vivo uptake and accumulation in the brain with favorable kinetics. Chase studies using 30 mg/kg levetiracetam confirmed that in vivo brain uptake of [ 18 F]MNI-1126/[ 18 F]SDM-8 was reversible.
Conclusions: Taken together, these data suggest [ 18 F]MNI-1126/[ 18 F]SDM-8 (since renamed as [ 18 F]SynVesT-1) characterized via an in vitro screening cascade provided a measurable in vivo SV2A specific signal in the rodent brain. This tracer as well as the close analog [ 18 F]SDM-2 (since renamed as [ 18 F]SynVesT-2) is currently undergoing further evaluation in preclinical and clinical studies.
Databáze: MEDLINE
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