Discovery of Heterocyclic Nonacetamide Synaptic Vesicle Protein 2A (SV2A) Ligands with Single-Digit Nanomolar Potency: Opening Avenues towards the First SV2A Positron Emission Tomography (PET) Ligands

• Published in: ChemMedChem Vol. 9; no. 4; pp. 693 - 698
• Main Authors: Mercier, Joël, Archen, Laurence, Bollu, Véronique, Carré, Stéphane, Evrard, Yves, Jnoff, Eric, Kenda, Benoît, Lallemand, Bénédicte, Michel, Philippe, Montel, Florian, Moureau, Florence, Price, Nathalie, Quesnel, Yannick, Sauvage, Xavier, Valade, Anne, Provins, Laurent
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.04.2014; WILEY‐VCH Verlag; Wiley
• Subjects: Acetamides - chemical synthesis; Acetamides - chemistry; Animals; Chemistry, Medicinal; Drug Discovery; epilepsy; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Humans; imaging agents; levetiracetam; Life Sciences & Biomedicine; Ligands; Male; Membrane Glycoproteins - analysis; Membrane Glycoproteins - metabolism; Models, Molecular; Molecular Structure; Nerve Tissue Proteins - analysis; Nerve Tissue Proteins - metabolism; Pharmacology & Pharmacy; positron emission tomography (PET); Positron-Emission Tomography; Radioactive Tracers; Rats; Rats, Wistar; Science & Technology; synaptic vesicle proteins; tracers; epilepsy; SITE; positron emission tomography (PET); NEUROTRANSMITTER RELEASE; SYNAPTOTAGMIN; tracers; DRUG DISCOVERY; imaging agents; BINDING CHARACTERISTICS; SEIZURES; synaptic vesicle proteins; BRIVARACETAM UCB-34714; RAT-BRAIN; levetiracetam
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201300482

The role of the synaptic vesicle protein 2A (SV2A) protein, target of the antiepileptic drug levetiracetam, is still mostly unknown. Considering its potential to provide in vivo functional insights into the role of SV2A in epileptic patients, the development of an SV2A positron emission tomography (PET) tracer has been undertaken. Using a 3D pharmacophore model based on close analogues of levetiracetam, we report the rationale design of three heterocyclic non‐acetamide lead compounds, UCB‐A, UCB‐H and UCB‐J, the first single‐digit nanomolar SV2A ligands with suitable properties for development as PET tracers. Avenues towards imaging…︁of synaptic vesicle protein 2A (SV2A) in vivo were opened after the rationale discovery of the first non‐acetamide SV2A ligands, displaying single‐digit nanomolar potency, using a 3D pharmacophore model. An extensive profiling of the most potent compounds allowed the identification of three leads (see figure) as potential candidates for positron emission tomography (PET) ligand development.