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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.

Author information

1
Codiak Biosciences, 500 Technology Square, 9th Floor, Cambridge, MA, 02139, USA. shil.patel@codiakbio.com.
2
Centre for Addiction and Mental Health, University of Toronto, 250 College Street, Toronto, ON, M5T 1R8, Canada.
3
Eisai Inc., 100 Tice Blvd, Woodcliff Lake, NJ, 07677, USA.
4
Invicro, LLC, 27 Drydock Ave. 7th Floor West, Boston, MA, 02210, USA.
5
PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, 801 Howard Avenue, New Haven, CT, 06510, USA.
6
Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
7
Department of Interventional Radiology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan Second Road, Yuexiu District, Guangzhou, 510080, China.

Abstract

PURPOSE:

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.

PROCEDURES:

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.

RESULTS:

[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.

CONCLUSIONS:

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.

KEYWORDS:

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

PMID:
31728839
DOI:
10.1007/s11307-019-01428-0

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