The data further support the potential of GABAA alpha5 receptors as a target for cognition-enhancing drugs. The dual binding and functional selectivity offers an ideal profile for cognition-enhancing effects without the unwanted side effects associated with activity at other GABAA receptor subtypes.

Background and purpose:The OX2 receptor is a G-protein-coupled receptor that is abundantly found in the tuberomammillary nucleus, an important site for the regulation of the sleep-wake state. Herein, we describe the in vitro and in vivo properties of a selective OX2 receptor antagonist, EMPA, injected i.p. in rats during the active phase, reduced LMA dose-dependently. EMPA did not impair performance of rats in the rotarod procedure. Conclusions and implications:EMPA is a high-affinity, reversible and selective OX2 receptor antagonist, active in vivo, which should prove useful for analysis of OX2 receptor function.

Aggregates of tau and beta amyloid (Aβ) plaques constitute the histopathological hallmarks of Alzheimer's disease and are prominent targets for novel therapeutics as well as for biomarkers for diagnostic in vivo imaging. In recent years much attention has been devoted to the discovery and development of new PET tracers to image tau aggregates in the living human brain. Access to a selective PET tracer to image and quantify tau aggregates represents a unique tool to support the development of any novel therapeutic agent targeting pathological forms of tau. The objective of the study described herein was to identify such a novel radiotracer. As a result of this work, we discovered three novel PET tracers (2-(4-[C]methoxyphenyl)imidazo[1,2-a]pyridin-7-amine 7 ([C]RO6924963), N-[C]methyl-2-(3-methylphenyl)imidazo[1,2-a]pyrimidin-7-amine 8 ([C]RO6931643), and [F]2-(6-fluoropyridin-3-yl)pyrrolo[2,3-b:4,5-c']dipyridine 9 ([F]RO6958948)) with high affinity for tau neurofibrillary tangles, excellent selectivity against Aβ plaques, and appropriate pharmacokinetic and metabolic properties in mice and non-human primates.

The late-stage fluorination of common synthetic building blocks and drug leads is an appealing reaction for medicinal chemistry. In particular, fluorination of benzylic C-H bonds provides a means to attenuate drug metabolism at this metabolically labile position. Here we report two complimentary strategies for the direct fluorination of benzylic C-H bonds using N-fluorobenzenesulfonimide and either a decatungstate photocatalyst or AIBN-initiation.

Straightforward access toward previously unreported substituted, heterocyclic spiro[3.3]heptanes is disclosed. These spirocyclic systems may be considered as alternatives to 1,3-heteroatom-substituted cyclohexanes, which are otherwise insufficiently stable to allow their use in drug discovery. Conformational details are discussed on the basis of X-ray crystallographic structures.