Radiolabeled benzoxazinoles - a unique beta-amyloid PET-tracer class allowing the dichotomous detection of parenchymal and vascular beta-amyloid deposits
Medical Physics, Biomedical Technology
Nuclear Medicine, Radiotherapy, Radiobiology
Final Report Abstract
Our work shows that fluoroethyl resorufin preferentially binds to vascular Aβ as shown by in vitro fluorescence imaging and in vitro fibril binding experiments. In vitro autoradiography experiments confirm a specific and selective binding to a model with CAA pathology. In vivo, [18F]FER shows a good biodistribution with BBB penetration and brain SUVs of 1.5 post i.v. injection (desired > 1) and a fast clearance with a half-life of t1/2 = 3 min (desired < 30 min). Thus, [18F]fluoroethyl resorufin clearly qualifies as a candidate for further preclinical and clinical development. Metabolite analysis of [18F]FER in mice and rats revealed a main metabolite detectable in the brain, with only 3 % of the parent compound remaining at 5 minutes, which may hamper the tracer quantification in the brain. Despite the detection of BBB-penetrating metabolites in rodents, rapid metabolism in small animals may not be a criterion of exclusion of a potential PET ligand for the application in humans as BBB penetration of the radio-metabolite as well as the metabolism of the compound itself can be largely species-dependent. Several studies have for example demonstrated species differences in the distribution and specificity of transporters such as the P-glycoprotein (P-gp). In addition, [11C]PIB, the gold standard for amyloid PET imaging in human AD shows high radio-metabolite formation in rat brains in contrast to only minor amounts in brains of mice, humans and baboons. Therefore, our goal is to further validate this promising candidate as a potential PET tracer to image vascular Aβ in the brain by reducing the brain metabolism and test it in pigs. This will be achieved by synthesis, radiolabeling and characterization of new derivatives with eliminated putative metabolism routes but conservation of the binding-relevant core of the molecule. We will further determine specificity and selectivity in human brain slices of confirmed CAA. If the obtained data meet the criteria for a successful CAA PET ligand, we will continue with proof of concept analysis using animal models of amyloidosis with and without CAA pathology. To achieve these goals, we applied for further DFG funding.
