Identification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer's Disease with Positron Emission Tomography.

Aggregates of tau and beta amyloid (Aß) 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-[11C]methoxyphenyl)imidazo[1,2-a]pyridin-7-amine 7 ([11C]RO6924963), N-[11C]methyl-2-(3-methylphenyl)imidazo[1,2-a]pyrimidin-7-amine 8 ([11C]RO6931643), and [18F]2-(6-fluoropyridin-3-yl)pyrrolo[2,3-b:4,5-c']dipyridine 9 ([18F]RO6958948)) with high affinity for tau neurofibrillary tangles, excellent selectivity against Aß plaques, and appropriate pharmacokinetic and metabolic properties in mice and non-human primates.

A Real-World Perspective on Molecular Design.

We present a series of small molecule drug discovery case studies where computational methods were prospectively employed to impact Roche research projects, with the aim of highlighting those methods that provide real added value. Our brief accounts encompass a broad range of methods and techniques applied to a variety of enzymes and receptors. Most of these are based on judicious application of knowledge about molecular conformations and interactions: filling of lipophilic pockets to gain affinity or selectivity, addition of polar substituents, scaffold hopping, transfer of SAR, conformation analysis, and molecular overlays. A case study of sequence-driven focused screening is presented to illustrate how appropriate preprocessing of information enables effective exploitation of prior knowledge. We conclude that qualitative statements enabling chemists to focus on promising regions of chemical space are often more impactful than quantitative prediction.

Tandem Protocol for the Stereoselective Synthesis of Different Polyfunctional beta-Amino Acids and 3-Amino-Substituted Carbohydrates.

Conjugate addition of homochiral amidocuprates or lithium amides based on (R)-N-(1-phenylethyl)(trimethylsilyl)amine to alpha,beta-unsaturated esters proceeds stereoselectively and allows the synthesis of beta-amino acids. Trapping of the intermediate ester enolate with D(2)O affords the corresponding deuterated compounds. anti-alpha-Alkyl-beta-amino acids are obtained stereoselectively after transmetalation of the lithium/copper ester enolate to the titanium ester enolate and trapping with carbon electrophiles. Both diastereomers of beta-homothreonine, other precursors of 3-amino-substituted carbohydrates, and stereoselectively in position 2 deuterated analogues are formed from enantiomerically pure gamma-alkoxy-substituted enoates. The product distribution observed is complementary to published results regarding 1,4-addition to gamma-silyloxy-substituted enoates. The anti/syn selectivity can be explained by assuming transition state geometries where the delivery of the nitrogen nucleophile is controlled by lithium "chelation" between reagent and substrate. In one case the product configuration can be controlled by the reagent irrespective of the substrate stereochemistry; in other cases the topicity of the addition is complementary to published results. For instance, erythro- or threo-configured 2,3-dideoxy-3-aminopentoses are accessible via this route.