Located in presynaptic cholinergic nerve terminals, the vesicular acetylcholine transporter (VACh... more Located in presynaptic cholinergic nerve terminals, the vesicular acetylcholine transporter (VAChT) represents a potential target for quantitative visualization of early degeneration of cholinergic neurons in Alzheimer's disease using PET. Benzovesamicol derivatives are proposed as radioligands for this purpose. We report QSAR studies of vesamicol and benzovesamicol derivatives taking into account the stereoselectivity of the VAChT binding site. Use of different data sets and different models in this study revealed that both enantiomers of 5-fluoro-3-(4-phenyl-piperidin-1-yl)-1,2,3,4-tetrahydro-naphthalen-2-ol (5-FBVM) are promising candidates, with predicted VAChT affinities between 6.1 and 0.05 nM. The synthesis of enantiopure (R,R)- and (S,S)-5-FBVM and their corresponding triazene precursors for future radiofluorination is reported. Both enantiomers exhibited high in vitro affinity for VAChT [(+)-5-FBVM: K(i)=6.95 nM and (-)-5-FBVM: K(i)=3.68 nM] and were selective for σ(2) receptors (∼70-fold), only (+)-5-FBVM is selective for σ(1) receptors (∼fivefold). These initial results suggest that (+)-(S,S)-5-FBVM warrants further investigation as a potential radioligand for in vivo PET imaging of cholinergic nerve terminals.
ABSTRACT Efficient regulatory mechanisms that induce innovation, co-operation and deter competiti... more ABSTRACT Efficient regulatory mechanisms that induce innovation, co-operation and deter competition law infringements have recently been the subject of growing attention. Competition is essential to the innovation process which in general terms enables entrepreneurship. But so too is co-operation between firms which requires an exchange of information and may lead to inefficient collusive behaviour. The optimal trade-off between the provision of stable entrepreneurial incentives and the new European competition law’s reform with the self-assessment system has been largely missing from the current scholarly debate. This paper identifies the unintended horizontal side effects of this new self-assessment system upon the entrepreneurial activity, offers a legal evaluation of the optimal entrepreneurial incentive mechanisms and provides legal and economics arguments for an improved regulatory response.
Located in presynaptic cholinergic nerve terminals, the vesicular acetylcholine transporter (VACh... more Located in presynaptic cholinergic nerve terminals, the vesicular acetylcholine transporter (VAChT) represents a potential target for quantitative visualization of early degeneration of cholinergic neurons in Alzheimer's disease using PET. Benzovesamicol derivatives are proposed as radioligands for this purpose. We report QSAR studies of vesamicol and benzovesamicol derivatives taking into account the stereoselectivity of the VAChT binding site. Use of different data sets and different models in this study revealed that both enantiomers of 5-fluoro-3-(4-phenyl-piperidin-1-yl)-1,2,3,4-tetrahydro-naphthalen-2-ol (5-FBVM) are promising candidates, with predicted VAChT affinities between 6.1 and 0.05 nM. The synthesis of enantiopure (R,R)- and (S,S)-5-FBVM and their corresponding triazene precursors for future radiofluorination is reported. Both enantiomers exhibited high in vitro affinity for VAChT [(+)-5-FBVM: K(i)=6.95 nM and (-)-5-FBVM: K(i)=3.68 nM] and were selective for σ(2) receptors (∼70-fold), only (+)-5-FBVM is selective for σ(1) receptors (∼fivefold). These initial results suggest that (+)-(S,S)-5-FBVM warrants further investigation as a potential radioligand for in vivo PET imaging of cholinergic nerve terminals.
ABSTRACT Efficient regulatory mechanisms that induce innovation, co-operation and deter competiti... more ABSTRACT Efficient regulatory mechanisms that induce innovation, co-operation and deter competition law infringements have recently been the subject of growing attention. Competition is essential to the innovation process which in general terms enables entrepreneurship. But so too is co-operation between firms which requires an exchange of information and may lead to inefficient collusive behaviour. The optimal trade-off between the provision of stable entrepreneurial incentives and the new European competition law’s reform with the self-assessment system has been largely missing from the current scholarly debate. This paper identifies the unintended horizontal side effects of this new self-assessment system upon the entrepreneurial activity, offers a legal evaluation of the optimal entrepreneurial incentive mechanisms and provides legal and economics arguments for an improved regulatory response.
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Papers by Mitja Kovac