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Mol Imaging Biol. 2019 Nov 14. doi: 10.1007/s11307-019-01428-0. [Epub ahead of print]

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.

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Codiak Biosciences, 500 Technology Square, 9th Floor, Cambridge, MA, 02139, USA.
Centre for Addiction and Mental Health, University of Toronto, 250 College Street, Toronto, ON, M5T 1R8, Canada.
Eisai Inc., 100 Tice Blvd, Woodcliff Lake, NJ, 07677, USA.
Invicro, LLC, 27 Drydock Ave. 7th Floor West, Boston, MA, 02210, USA.
PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 801 Howard Avenue, New Haven, CT, 06510, USA.
Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
Department of Interventional Radiology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan Second Road, Yuexiu District, Guangzhou, 510080, China.



Current synaptic vesicle 2A (SV2A) positron emission tomography (PET) imaging agents include the nanomolar affinity probes [11C]UCB-J and [18F]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.


Radioligand binding methods were employed in mammalian brain homogenates to determine the SV2A affinity (Kd) and maximal binding capacity (Bmax) of [3H]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.


[3H]UCB-J bound with high affinity to a single population of sites in the rat brain (Kd = 2.6 ± 0.25 nM; Bmax = 810 ± 25 fmol/mg protein) and control human cortex (Kd = 2.9 ± 0.54 nM; Bmax = 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 [18F]MNI-1126/[18F]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 [18F]MNI-1126/[18F]SDM-8 was reversible.


Taken together, these data suggest [18F]MNI-1126/[18F]SDM-8 (since renamed as [18F]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 [18F]SDM-2 (since renamed as [18F]SynVesT-2) is currently undergoing further evaluation in preclinical and clinical studies.


Micro-PET imaging; PET radioligand; Preclinical characterization; Radioligand binding; SV2A


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