(S)-alpha-ethyl-2-oxopyrrolidine acetamide 2 (levetiracetam, Keppra, UCB S.A.), a structural analogue of piracetam, has recently been approved as an add-on treatment of refractory partial onset seizures in adults. This drug appears to combine significant efficacy and high tolerability due to a unique mechanism of action. The latter relates to a brain-specific binding site for 2 (LBS for levetiracetam binding site) that probably plays a major role in its antiepileptic properties. Using this novel molecular target, we initiated a drug-discovery program searching for ligands with significant affinity to LBS with the aim to characterize their therapeutic potential in epilepsy and other central nervous system diseases. We systematically investigated the various positions of the pyrrolidone acetamide scaffold. We found that (i) the carboxamide moiety on 2 is essential for affinity; (ii) among 100 different side chains, the preferred substitution alpha to the carboxamide is an ethyl group with the (S)-configuration; (iii) the 2-oxopyrrolidine ring is preferred over piperidine analogues or acyclic compounds; (iv) substitution of positions 3 or 5 of the lactam ring decreases the LBS affinity; and (v) 4-substitution of the lactam ring by small hydrophobic groups improves the in vitro and in vivo potency. Six interesting candidates substituted in the 4-position have been shown to be more potent antiseizure agents in vivo than 2. Further pharmacological studies from our group led to the selection of (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]butanamide 83alpha (ucb 34714) as the most interesting candidate. It is approximately 10 times more potent than 2 as an antiseizure agent in audiogenic seizure-prone mice. A clinical phase I program has been successfully concluded and 83alpha will commence several phase II trials during 2003.

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.

Despite ag rowing interest in CHF 2 in medicinal chemistry,there is alackofefficient methods for the insertion of CHF 18 Fi nto druglike compounds.H erein described is ap hotoredoxf lowr eaction for 18 F-difluoromethylation of Nheteroaromatics that are widely used in medicinal chemistry. Following the two-step synthesis for anew 18 F-difluoromethylation reagent, the photoredoxreaction is completed within two minutes and proceeds by CÀHa ctivation, circumventing the need for pre-functionalizationo ft he substrate.T he method is operationally simple and affords straightforwarda ccess to radiolabeled N-heteroaromatics with high molar activity suitable for biological in vivo studies and clinical application.

Research on the therapeutic applications of the histamine H3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R agonists have received less attention despite their potential use in several disease areas. The lower availability of H3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H3R activation. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H3R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12-31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H 3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H3R research.

Visible light photocatalysis allows the introduction of the sulfone functional group to anilines under mild reaction conditions, without the need for pre-functionalization.

We recently reported a new method for the 18 F-difluoromethylation of N-heteroaromatics for PET imaging. The method involves the synthesis of a new 18 F-difluoromethylating reagent 2-[ 18 F]((difluoromethyl)sulfonyl)benzo[d]thiazole and a flow photoredox 18 Fdifluoromethylation. For preclinical development and human Positron Emission Tomography (PET) studies with new radiotracers, an automation of the process is mandatory, mostly to avoid radioprotection issues, due to the use of high amounts of radioactivity and to ensure a better reliability of the production. We hereby describe the automation of this 18 Fdifluoromethylation method, on a model substrate, Acyclovir, on a commercially available AllinOne (AIO) synthesizer from Trasis. The whole process is completed in 95 minutes and provides radiolabeled Acyclovir with a molar activity of 35 GBq/µmol. This automated protocol can be implemented for the 18 F-difluoromethylation of a wide range of Nheteroaromatics compounds typically found in medicinal chemistry.

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