| Institution: | 1. Biomedical Systems, Center for Health & Bioresources, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria;2. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria;3. Department of Neuro-/Pathology, University of Oslo (UiO) and Oslo University Hospital (OUS), Oslo, Norway;4. LIED, University of Lübeck, Germany;5. Leibniz-Institute of Plant Biochemistry, Halle, Germany;6. Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria;1. National Institute of Radiological Science, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan;2. SHI Accelerator Service Ltd., Tokyo 141-0032, Japan;3. Tokyo Nuclear Services Ltd., Tokyo 110-0016, Japan;4. Molecular Neuroimaging LLC., New Haven, CT06510, USA;1. Institute of Neuroscience and Medicine, INM-2, Forschungszentrum Jülich GmbH, Jülich, Germany;2. Institute of Neuroscience and Medicine, INM-4, Forschungszentrum Jülich GmbH, Jülich, Germany;3. Neurological Department, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany |
| Abstract: | Poly(ADP-ribose)polymerase-1 inhibitor (PARPi) AZD2461 was designed to be a weak P-glycoprotein (P-gp) analogue of FDA approved olaparib. With this chemical property in mind, we utilized the AZD2461 ligand architecture to develop a CNS penetrant and PARP-1 selective imaging probe, in order to investigate PARP-1 mediated neuroinflammation and neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. Our work led to the identification of several high-affinity PARPi, including AZD2461 congener 9e (PARP-1 IC50 = 3.9 ± 1.2 nM), which was further evaluated as a potential 18F-PET brain imaging probe. However, despite the similar molecular scaffolds of 9e and AZD2461, our studies revealed non-appreciable brain-uptake of 18F]9e in non-human primates, suggesting AZD2461 to be non-CNS penetrant. |
