Expanding the Azaspiro[3.3]heptane Family: Synthesis of Novel Highly Functionalized Building Blocks

The preparation of versatile azaspiro[3.3]heptanes carrying multiple exit vectors is disclosed. Expedient synthetic routes enable the straightforward access to these novel modules that are expected to have significance in drug discovery and design

Expanding the Azaspiro[3.3]heptane Family: Synthesis of Novel Highly Functionalized Building Blocks

The preparation of versatile azaspiro[3.3]heptanes carrying multiple exit vectors is disclosed. Expedient synthetic routes enable the straightforward access to these novel modules that are expected to have significance in drug discovery and design

Bis(arylvinyl)pyrazines, -pyrimidines, and -pyridazines As Imaging Agents for Tau Fibrils and β‑Amyloid Plaques in Alzheimer’s Disease Models

The in vivo diagnosis of Alzheimer’s disease (AD) is of high socioeconomic interest and remains a demanding field of research. The biopathological hallmarks of the disease are extracellular plaques consisting of aggregated β-amyloid peptides (Aβ) and tau protein derived intracellular tangles. Here we report the synthesis and evaluation of fluorescent pyrazine, pyrimidine,and pyridazine derivatives in vitro and in vivo aiming at a tau-based diagnosis of AD. The probes were pre-evaluated on human brain tissue by fluorescence microscopy and were found to label all known disease-related alterations at high contrast and specificity. To quantify the binding affinity, a new thiazine red displacement assay was developed and selected candidates were toxicologically profiled. The application in transgenic mouse models demonstrated bioavailability and brain permeability for one compound. In the course of histological testing, we discovered an AD-related deposition of tau aggregates in the Bowman’s glands of the olfactory epithelium, which holds potential for an endoscopic diagnosis of AD in the olfactory system

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

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-[¹¹C]­methoxyphenyl)­imidazo­[1,2-<i>a</i>]­pyridin-7-amine <b>7</b> ([¹¹C]­RO6924963), <i>N</i>-[¹¹C]­methyl-2-(3-methylphenyl)­imidazo­[1,2-<i>a</i>]­pyrimidin-7-amine <b>8</b> ([¹¹C]­RO6931643), and [¹⁸F]­2-(6-fluoropyridin-3-yl)­pyrrolo­[2,3-<i>b</i>:4,5-<i>c</i>′]­dipyridine <b>9</b> ([¹⁸F]­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