title: Evaluation of TSPO PET Ligands [18F]VUIIS1009A and [18F]VUIIS1009B: Tracers for Cancer Imaging.
abstract: 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.
  
  
  
  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 2D1H-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.
  
  
  
  Both VUIIS1009A (3A) and VUIIS1009B (3B) were found to exhibit exceptional binding affinity to TSPO, with observed IC50values 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.
  
  
  
  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.
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN, 37232, USA.|Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.|Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.|Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, 201318, China.
authors.forename: Dewei
authors.initials: D
authors.lastname: Tang
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN, 37232, USA.|Interdisciplinary Materials Science Program, Department of Physics and Astronomy, Vanderbilt University, Nashville, TN, 37240, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Buck
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN, 37232, USA.|Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
authors.forename: Mohamed Noor
authors.initials: MN
authors.lastname: Tantawy
authors.affiliation: Center for Structural Biology (CSB), Vanderbilt University, Nashville, TN, 37205, USA.|Department of Chemistry, Vanderbilt University, Nashville, TN, 37235, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.|Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37235, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Harp
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN, 37232, USA.|Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nickels
authors.affiliation: Center for Structural Biology (CSB), Vanderbilt University, Nashville, TN, 37205, USA.|Department of Chemistry, Vanderbilt University, Nashville, TN, 37235, USA.|Vanderbilt Institute of Chemical Biology (VICB), Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Meiler
authors.affiliation: Vanderbilt University Institute of Imaging Science (VUIIS), Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.|Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.|Department of Chemistry, Vanderbilt University, Nashville, TN, 37235, USA. henry.c.manning@vanderbilt.edu.|Program in Chemical and Physical Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.|Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.|Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.|Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. henry.c.manning@vanderbilt.edu.
authors.forename: H Charles
authors.initials: HC
authors.lastname: Manning
mesh_terms: D000818:Animals; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003952:Diagnostic Imaging; D005462:Fluorine Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics; D005910:Glioma / Q000000981:diagnostic imaging* / Q000473:pathology; D008024:Ligands; D008297:Male; D008810:Mice, Inbred C57BL; D049268:Positron-Emission Tomography; D051381:Rats; D014018:Tissue Distribution; D051598:Whole Body Imaging
chemical_list: D001798:Blood Proteins; D002352:Carrier Proteins; D005462:Fluorine Radioisotopes; D008024:Ligands
keywords: Cancer imaging; PET; Precision medicine; TSPO; VUIIS1009A; VUIIS1009B