Evaluation of TSPO PET Ligands [18F]VUIIS1009A and [18F]VUIIS1009B: Tracers for Cancer Imaging

Abstract

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, [18F]VUIIS1009A ([18F]3A) and [18F]VUIIS1009B ([18F]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 1H-15N heteronuclear single quantum coherence (HSQC) spectroscopy. In vivo biodistribution of [18F]VUIIS1009A and [18F]VUIIS1009B was carried out in healthy mice with and without radioligand displacement. Dynamic PET imaging data were acquired simultaneously with [18F]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 IC50 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. [18F]VUIIS1009A ([18F]3A) and [18F]VUIIS1009B ([18F]3B) exhibited similar biodistribution in healthy mice. In rats bearing C6 gliomas, both [18F]VUIIS1009A and [18F]VUIIS1009B exhibited greater binding potential (k3/k4) in tumor tissue compared to [18F]DPA-714. Interestingly, [18F]VUIIS1009B exhibited significantly greater tumor uptake (VT) than [18F]VUIIS1009A, which was attributed primarily to greater plasma-to-tumor extraction efficiency. Conclusions The novel PET ligand [18F]VUIIS1009B exhibits promising characteristics for imaging glioma; its superiority over [18F]VUIIS1009A, a regioisomer, appears to be primarily due to improved plasma extraction efficiency. Continued evaluation of [18F]VUIIS1009B as a high-affinity TSPO PET ligand for precision medicine appears warranted.

18F-VUIIS1009B Features a Superior Imaging Performance to 18F-DPA-714 in TSPO Density Characterization for Neuroinflammatory PET Imaging

“…Of these radiotracers, 18 F-VUIIS1009A and 18 F-VUIIS1009B demonstrate over 500-fold higher binding a nities when compared to the parent radiotracer 18 F-DPA-714. Imaging with these two radiotracers in C6 glioma model also demonstrates the superiority of 18 F-VUIIS1009B to 18 F-VUIIS1009A and 18 F-DPA-714, including higher BP ND , higher SNR and higher total distribution volume (V T ) [22].…”

“…Based on the scaffold of 18 F-DPA-714, many novel radiotracers have been developed and introduced in both clinical and preclinical TSPO PET imaging, including 18 F-DPA-C5yne [19], 18 F-VUIIS1008 [20,21], 18 F-VUIIS1009A/B [22], 18 F-FDPA [23], 18 F-VUIIS1018A [24,25]. Of these radiotracers, 18 F-VUIIS1009A and 18 F-VUIIS1009B demonstrate over 500-fold higher binding a nities when compared to the parent radiotracer 18 F-DPA-714.…”

Facile synthesis of SSR180575 and discovery of 7-chloro- N , N ,5-trimethyl-4-oxo-3(6-[ 18 F]fluoropyridin-2-yl)-3,5-dihydro-4 H -pyridazino[4,5- b ]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer

“…13 Subsequent in vivo studies of [ 18 F]- 2b demonstrated this agent to possess several properties for molecular imaging of TSPO-expressing cancers. 13,21 …”

“…Subsequent preclinical studies illuminated [ 18 F]- 14 as a promising, novel TSPO PET ligand for imaging glioma. Compared to previous TSPO PET ligands in oncology, the first generation ligand [ 11 C]PK11195 39 and the second generation ligands [ 18 F]PBR06, 19 [ 18 F]DPA-714, 12 and [ 18 F]VUIIS1008, 13,21 [ 18 F]- 14 has demonstrated improved binding affinity and in vivo imaging characteristics. These advantages, in addition to the in vivo stability and high signal-to-noise achieved between tumor and surrounding normal brain, suggest the potential of this PET ligand for detection of TSPO-expressing tumors in the brain and neuroinflammation.…”

“…These advantages, in addition to the in vivo stability and high signal-to-noise achieved between tumor and surrounding normal brain, suggest the potential of this PET ligand for detection of TSPO-expressing tumors in the brain and neuroinflammation. Future head-to-head comparisons between this tracer and emerging, potent TSPO ligands 13,21 are underway, as well as exploration of other promising applications in oncology, neuroinflammation, and other diseases.…”