Evaluationof 18F-FPPA as a PositronEmission Tomography Radioligand for Imaging CSF1R in LPS-Induced RatModel of Neuroinflammation

Abstract Noninvasive detection of microglia is crucial for monitoring their spatiotemporal dynamics and facilitating early medical intervention during the prodromal stages of these neuroinflammatory diseases. Colony-stimulating factor 1 receptor (CSF1R) is a promising imaging biomarker for microglia in neuroinflammation. However, currently developed CSF1R-targeted probes lack [18F]-labeled variants, and their stability, sensitivity, and specificity are all suboptimal to some extent. In our study, based on pyrrolopyrimidines(a distinct structure of CSF1R inhibitors), we developed the [18F]-labeled CSF1R-targeted probe-18F-FPPA (6-(4-(2-(2-(2-(fluoro-18F)ethoxy)ethoxy)ethoxy)phenyl)-N-methyl-N-(3-methylbenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine).18F-FPPA was synthesized with a radiochemical yield of 4–7%, molar activity of 30–70 GBq/μmol, and radiochemical purity exceeding 99%, which possesses excellent physicochemical properties, rapid blood pharmacokinetics (T1/2α = 2.50 min, T1/2β = 32.4 min), favorable invitro and in vivo stability, and a clear metabolic pathway via dual hepatobiliary and renal excretion. A marked uptake of 18F-FPPA was observed at the LPS injection site in the LPS group at 30–40 min postinjection. A decreased uptake also was observed in cold 19F-FPPA, BLZ945, and PLX3397 blocking groups (P < 0.05), and no obvious increase in the group of intraperitoneal injection of cyclosporine A (P > 0.05). The in vivo imaging and immunohistochemical results confirmed the specific uptake of 18F-FPPA by targeting CSF1R on microglia in inflamed tissues. Overall, our findings demonstrated that 18F-FPPA had great potential as a promising tracer for the imaging of neuroinflammatory diseases, while its unique binding profile also provides insights into CSF1R-targeted ligand development.