Sean W Reilly1, Laura N Puentes2, Alexander Schmitz1, Chia-Ju Hsieh1, Chi-Chang Weng1, Catherine Hou1, Shihong Li1, Yin-Ming Kuo1, Prashanth Padakanti1, Hsiaoju Lee1, Aladdin A Riad1, Mehran Makvandi3, Robert H Mach4. 1. Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA. 2. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104, USA. 3. Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: makvandi@pennmedicine.upenn.edu. 4. Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: rmach@mail.med.upenn.edu.
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.
Poly(ADP-ribose)polymerase-1 inhibitor (n class="Gene">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.
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