Design, Synthesis, and Evaluation of [¹⁸F]BIBD-300 as a Positron Emission Tomography Tracer for Poly(ADP-Ribose) Polymerase‑1

Compounds 8a–j were designed to adjust the mode of interaction and lipophilicity of FTT by scaffold hopping and changing the length of the alkoxy groups. Compounds 8a, 8d, 8g, and BIBD-300 were screened for high-affinity PARP-1 through enzyme inhibition assays and are worthy of further evaluation. PET imaging of MCF-7 subcutaneous tumors with moderate expression of PARP-1 showed that compared to [¹⁸F]­FTT, [¹⁸F]­8a, [¹⁸F]­8d, and [¹⁸F]­8g exhibited greater nonspecific uptake, a lower target-to-nontarget ratio, and severe defluorination, while [¹⁸F]­BIBD-300 exhibited lower nonspecific uptake and a greater target-to-nontarget ratio. PET imaging of 22Rv1 subcutaneous tumors, which highly express PARP-1, confirmed that the uptake of [¹⁸F]­BIBD-300 in normal organs, such as the liver, muscle, and bone, was lower than that of [¹⁸F]­FTT, and the ratio of tumor-to-muscle and tumor-to-liver [¹⁸F]­BIBD-300 was greater than that of [¹⁸F]­FTT. The biodistribution results in mice with MCF-7 and 22Rv1 subcutaneous tumors further validated the results of PET imaging. Unlike [¹⁸F]­FTT, which mainly relies on hepatobiliary clearance, [¹⁸F]­BIBD-300, which has lower lipophilicity, undergoes a partial shift from hepatobiliary to renal clearance, providing the possibility for [¹⁸F]­BIBD-300 to indicate liver cancer. The difference in the PET imaging results for [¹⁸F]­FTT, [¹⁸F]­BIBD-300, and [¹⁸F]­8j in 22Rv1 mice and the corresponding molecular docking results further confirmed that subtle structural modifications in lipophilicity greatly optimize the properties of the tracer. Cell uptake experiments also demonstrated that [¹⁸F]­BIBD-300 has a high affinity for PARP-1. Metabolized and unmetabolized [¹⁸F]­FTT and [¹⁸F]­BIBD-300 were detected in the brain, indicating that they could not accurately quantify the amount of PARP-1 in the brain. However, PET imaging of glioma showed that both [¹⁸F]­FTT and [¹⁸F]­BIBD-300 could accurately localize both in situ to C6 and U87MG tumors. Based on its potential advantages in the diagnosis of breast cancer, prostate cancer, and glioma, as well as liver cancer, [¹⁸F]­BIBD-300 is a new option for an excellent PARP-1 tracer.