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.
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.
Global Chemistry, UCB NewMedicines, UCB Pharma, Chemin du Foriest, B-1420 Braine-L'Alleud (Belgium). joel.mercier@ucb.com.
Joël
J
Mercier
Laurence
L
Archen
Véronique
V
Bollu
Stéphane
S
Carré
Yves
Y
Evrard
Eric
E
Jnoff
Benoît
B
Kenda
Bénédicte
B
Lallemand
Philippe
P
Michel
Florian
F
Montel
Florence
F
Moureau
Nathalie
N
Price
Yannick
Y
Quesnel
Xavier
X
Sauvage
Anne
A
Valade
Laurent
L
Provins
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D055808:Drug Discovery; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000032:analysis* / Q000378:metabolism; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D051381:Rats; D017208:Rats, Wistar
D000081:Acetamides; D006571:Heterocyclic Compounds; D008024:Ligands; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D011849:Radioactive Tracers; C076414:SV2A protein, human
epilepsy; imaging agents; levetiracetam; positron emission tomography (PET); synaptic vesicle proteins; tracers