PURPOSE - Positron emission tomography (PET) ligands targeting translocator protein (TSPO) are potential imaging diagnostics of cancer. In this study, we report two novel, high-affinity TSPO PET ligands that are 5,7 regioisomers, [F]VUIIS1009A ([F]3A) and [F]VUIIS1009B ([F]3B), and their initial in vitro and in vivo evaluation in healthy mice and glioma-bearing rats.
PROCEDURES - VUIIS1009A/B was synthesized and confirmed by X-ray crystallography. Interactions between TSPO binding pocket and novel ligands were evaluated and compared with contemporary TSPO ligands using 2D H-N heteronuclear single quantum coherence (HSQC) spectroscopy. In vivo biodistribution of [F]VUIIS1009A and [F]VUIIS1009B was carried out in healthy mice with and without radioligand displacement. Dynamic PET imaging data were acquired simultaneously with [F]VUIIS1009A/B injections in glioma-bearing rats, with binding reversibility and specificity evaluated by radioligand displacement. In vivo radiometabolite analysis was performed using radio-TLC, and quantitative analysis of PET data was performed using metabolite-corrected arterial input functions. Imaging was validated with histology and immunohistochemistry.
RESULTS - Both VUIIS1009A (3A) and VUIIS1009B (3B) were found to exhibit exceptional binding affinity to TSPO, with observed IC values against PK11195 approximately 500-fold lower than DPA-714. However, HSQC NMR suggested that VUIIS1009A and VUIIS1009B share a common binding pocket within mammalian TSPO (mTSPO) as DPA-714 and to a lesser extent, PK11195. [F]VUIIS1009A ([F]3A) and [F]VUIIS1009B ([F]3B) exhibited similar biodistribution in healthy mice. In rats bearing C6 gliomas, both [F]VUIIS1009A and [F]VUIIS1009B exhibited greater binding potential (k /k )in tumor tissue compared to [F]DPA-714. Interestingly, [F]VUIIS1009B exhibited significantly greater tumor uptake (V ) than [F]VUIIS1009A, which was attributed primarily to greater plasma-to-tumor extraction efficiency.
CONCLUSIONS - The novel PET ligand [F]VUIIS1009B exhibits promising characteristics for imaging glioma; its superiority over [F]VUIIS1009A, a regioisomer, appears to be primarily due to improved plasma extraction efficiency. Continued evaluation of [F]VUIIS1009B as a high-affinity TSPO PET ligand for precision medicine appears warranted.