PET radiotracer targeting the complement C3a receptor

Background: Positron-emission tomography (PET) imaging of the complement system could advance understanding of the innate immune system in central nervous system (CNS) diseases and development of new drugs. The goal of this study was to develop a PET radiotracer targeting the C3a receptor (C3aR) of the complement system. Methods: C3aR radiotracer [¹⁸F]1 was synthesized in one step. Imaging properties of the radiotracer in the brain were tested in ex vivo experiments in mice. Results: [¹⁸F]1 was radiolabeled with radiochemical yield of 4 %, radiochemical purity >95 % and molar activity ~155 GBq/μmol. In control mice [¹⁸F]1 demonstrated high brain uptake (9 %ID/g tissue) which gradually increased over the 90 min of the study period and represented mainly non-specific binding. The C3aR specificity (18 %) of [¹⁸F]1 binding in the brain of control mice was determined in a blocking experiment. The brain uptake of [¹⁸F]1 was significantly increased (~2 – fold) in a murine model of neuroinflammation [lipopolysaccharide (LPS) – treated mice]. The blocking experiments in LPS-treated mice showed a dose-dependent reduction in whole-brain uptake of [¹⁸F]1 demonstrating that the blocked binding is partially specific (43 %) and dependent upon C3aR. This study demonstrated the feasibility of development a PET radiotracer for specific imaging of C3aR in neuroinflammation. However, [¹⁸F]1 is suboptimal for further studies, because of its insufficient specific binding in neuroinflammation model, high non-specific binding and slow irreversible kinetics in the mouse brain. Future research should focus on developing of optimized C3aR PET tracers with improved specific binding, reduced non-specific binding, reversible pharmacokinetics and, also, better radiochemistry.