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

Dewei Tang; Jun Li; Jason R Buck; Mohamed Noor Tantawy; Yan Xia; Joel M Harp; Michael L Nickels; Jens Meiler; H Charles Manning

doi:10.1007/s11307-016-1027-9

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

Mol Imaging Biol. 2017 Aug;19(4):578-588. doi: 10.1007/s11307-016-1027-9.

Authors

Dewei Tang^{1

2

3

4}, Jun Li^{1

5}, Jason R Buck¹, Mohamed Noor Tantawy^{1

2}, Yan Xia^{6

7}, Joel M Harp^{8

9}, Michael L Nickels^{1

2}, Jens Meiler^{6

7

10}, H Charles Manning^{11

12

13

14

15

16

17}

Affiliations

¹ Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
² Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
³ Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
⁴ Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China.
⁵ Interdisciplinary Materials Science Program, Department of Physics and Astronomy, Vanderbilt University, Nashville, TN, 37240, USA.
⁶ Center for Structural Biology (CSB), Vanderbilt University, Nashville, TN, 37205, USA.
⁷ Department of Chemistry, Vanderbilt University, Nashville, TN, 37235, USA.
⁸ Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
⁹ Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA.
¹⁰ Vanderbilt Institute of Chemical Biology (VICB), Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
¹¹ Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.
¹² Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.
¹³ Department of Chemistry, Vanderbilt University, Nashville, TN, 37235, USA. henry.c.manning@vanderbilt.edu.
¹⁴ Program in Chemical and Physical Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.
¹⁵ Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.
¹⁶ Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.
¹⁷ Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.

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 (k ₃/k ₄)in tumor tissue compared to [¹⁸F]DPA-714. Interestingly, [¹⁸F]VUIIS1009B exhibited significantly greater tumor uptake (V _T) 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.

Keywords: Cancer imaging; PET; Precision medicine; TSPO; VUIIS1009A; VUIIS1009B.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites
Blood Proteins / metabolism
Carrier Proteins / metabolism*
Cell Line, Tumor
Diagnostic Imaging*
Fluorine Radioisotopes / chemistry*
Fluorine Radioisotopes / pharmacokinetics
Glioma / diagnostic imaging*
Glioma / pathology
Ligands
Male
Mice, Inbred C57BL
Positron-Emission Tomography*
Rats
Tissue Distribution
Whole Body Imaging

Substances

Blood Proteins
Carrier Proteins
Fluorine Radioisotopes
Ligands

Abstract

Publication types

MeSH terms

Substances

Grants and funding