The discovery and development of disease modifying therapeutics for neurodegenerative diseases, such as Alzheimer’s disease (AD), remains a significant unmet medical need for human health. The main challenge has been the identification of disease relevant biomarkers that provide confidence in measuring therapeutic effects. Histopathalogical analysis from human AD brain tissue has shown that the abundance of aggregated tau proteins, in the form of neurofibrillary tangles (NFTs), is a better correlate for disease progression and cognitive decline. Therefore, the discovery of a positron emission tomography (PET) imaging agent for NFTs represents a valuable clinical tool to quantify changes in tau pathology and determine the effects of novel drug candidates.<br/><br/>This presentation will outline the challenges and new opportunities for synthetic chemistry to enable the discovery of clinical tools, using the discovery of MK–6240 as a case study. Within our efforts we encountered limitations with the current framework of clinically translatable radiochemical methods to introduce the F–18 radionuclide to simple heterocyclic ring systems. A deeper understanding of the stereoelectronic effects within the privileged pyrrolo–pyridine core of MK–6240 was essential for the strategic selection of precursors for F-18 incorporation. The successful synthesis of the optimal precursor and application of the best radiochemical synthesis to support preclinical non-human primate imaging studies, and early human clinical studies will be described.

New opportunities for synthetic chemistry to enable drug discovery: Discovery of [<sup>18</sup>F]MK-6240 a novel PET imaging agent for tau pathology

254th National Meeting (2017)

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New opportunities for synthetic chemistry to enable drug discovery: Discovery of [18F]MK-6240 a novel PET imaging agent for tau pathology

New opportunities for synthetic chemistry to enable drug discovery: Discovery of [¹⁸F]MK-6240 a novel PET imaging agent for tau pathology