Synthesis, Radiolabeling, and in Vitro and in Vivo Evaluation of [18F]ENL30: A Potential PET Radiotracer for the 5‑HT7 Receptor

The 5-HT7 receptor (5-HT7R) is involved in a broad range of physiological conditions and disorders. Currently, there is no validated clinical positron emission tomography (PET) tracer available; however, we have recently developed a promising 11C-labeled candidate. In this project, we aimed to further extend our efforts and develop an 18F-labeled derivative, coined [18F]­ENL30. Fluorine-18 has several advantages over carbon-11 especially within the preclinical phase, where a long half-life usually increases evaluation throughput. ENL30 was successfully synthesized in a low albeit sufficient overall yield. Radiolabeling succeeded with a radiochemical yield of approximately 4.5%. Subsequent preclinical PET studies revealed that [18F]­ENL30 binds specifically to the 5-HT7R but suffered from affinity to σ-receptors. Additionally, we identified [18F]­ENL30 to be a P-gp substrate in rats. However, we believe that [18F]­ENL30 may prove to be valuable in higher species that exhibit decreased P-gp dependency. If required, σ-receptor binding could, in such studies, be selectively blocked potentially allowing for selective 5-HT7R imaging.