Structure activity investigations of substituted quinazolines in the pursuit of a selective PDE1 PET ligand

• High Expression of PDE1A and PDE1B: These enzymes are highly expressed in neurons in brain regions associated with learning, memory, and cognitive processing. • Therapeutic Potential: PDE1 is a promising target for treating psychiatric and neurological diseases. • PET imaging is a Non-Invasive Translational Tool: PDE-specific radioligands enable non-invasive visualization and measurement of PDE1 in vivo using PET. • Discovery of Lu AF41228: This compound is a selective, highly permeable, and brain-penetrant PDE1 inhibitor. • Structural Analysis: The study includes the structure-activity relationship (SAR) for quinazolines and the X-ray structure of Lu AF41228 in complex with PDE1B and highlights that Methoxy-substiuent is not priviledged. • Radiolabeling and Evaluation: Lu AF41228 was radiolabeled with 11-C and tested as a potential PET ligand in pigs. • Conclusion: [11C]Lu AF41228 was found unsuitable as a PET ligand for PDE1B.