Evaluation of 18F-FPPA as a Positron Emission Tomography Radioligand for Imaging CSF1R in LPS-Induced Rat Model 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.