Radiolabeled benzoxazinoles - a unique beta-amyloid PET-tracer class allowing the dichotomous detection of parenchymal and vascular beta-amyloid deposits

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Alzheimer disease (AD) is an insidious, fatal disorder of the central nervous system (CNS) affecting 2/3 out of the estimated 35 mio people worldwide living with dementia. Key hallmarks of AD are the formation and accumulation of extracellular deposits through enzymatic cleavage of the amyloid precursor protein (APP), resulting in the formation of diverse and distinctly different amyloid deposits, depending on posttranslational peptide modifications and mutation status of the host. In patients with a genetic predisposition for AD, thus affected by a hereditary form of the disease, these processes take place already decades before first clinical symptoms are recognized. Only recently, it was discovered that the fragment length of the amyloid peptide, between 40 and 42 amino acids, predetermines the site of deposition in the transgenic mouse brain (parenchymal or vascular deposition). Thus, as the primary deposition site of amyloid species can be very different, it is well conceivable that the role in the development of the pathophysiological condition present in the diseased AD brain is distinctly divergent for cerebral amyloid angiopathy (CAA) and parenchymal amyloidosis (PEA). To unravel potentially differing pathogenic mechanisms of both amyloid deposits, it is crucial to develop a non-invasive screening method (in this proposal based on Positron Emission Tomography, PET) allowing for a quantitative and dichotomous detection of PEA and CAA, this is, however, so far not available. The strength of a non-invasive, in vivo diagnosis of mixed PEA/CAA states with PET or PET/MRI is the ability for 3D volume quantitation and a fully translational character of this technique. Moreover, to date no specific CAA PET-tracer is available and previously published CAA-imaging conceptual studies are unconvincing. Currently, we see a pressing need for a specific CAA tracer, as we have recently identified CAA as the major determinant behind quantitative loss of perfusion during the course of AD; thus CAA could have an important and, yet, underestimated impact on the progression of AD. As it turned out in the past decade, most of the published amyloid PET tracers are promiscuous amyloid imaging agents targeting several diffuse and dense deposits of both, APP and of non-APP nature. Therefore, there is still an urgent need for the development of improved diagnostic PET-tracers to image the disease progress in a reliable, comparable and amyloid-species differentiating manner. The hitherto neglected class of benzoxazinoles are characterized by the unique property of selective PEA or CAA affinity, depending on the lead structure design - a property that none of the other amyloid tracer classes is offering. Thus, the primary goal of this research proposal is to identify a structure design for a specific PEA and a specific CAA PET-tracer allowing their separate detection in the same subject.