Abstract

This multidisciplinary proposal seeks to develop and validate a novel class of cancer imaging biomarkers for rapid clinical deployment. Leveraging advances in basic and clinical cancer biology, innovative medicinal chemistry, and high-throughput, small molecule screening, our laboratory has identified tumor-selective translocator protein (TSPO) ligands that are promising candidates for further development as positron emission tomography (PET) imaging agents. TSPO is an 18 kDa high-affinity cholesterol- and drug-binding protein that participates in cholesterol metabolism, steroid biosynthesis, proliferation, and apoptosis. Elevated levels of TSPO are well-documented in oncology, where levels correlate with tumor proliferation, invasion, and metastasis. Furthermore, our laboratory has mechanistically linked TSPO ligand binding to mitogen-activated protein kinase (MAPK) signaling in glioma. Capitalizing upon this observation, we have shown that TSPO ligand PET can be used to evaluate MAPK pathway inhibition in this setting. Collectively, these data demonstrate the potential significance of TSPO ligand PET as a predictive imaging biomarker in oncology. The overall goal of this study is to develop clinically translatable, tumor-selective TSPO imaging ligands that facilitate improved detection, molecular characterization, and prognosis of human gliomas.
Our Specific Aims are [1] to optimize novel, tumor-selective TSPO ligand leads for in vivo PET imaging, [2] to develop methods for labeling promising TSPO ligands with the positron-emitting isotope fluorine-18, and [3] to evaluate promising TSPO imaging ligands in vivo.

Public Health Relevance

This multidisciplinary proposal seeks to develop, evaluate, and validate novel translocator protein (TSPO) positron emission tomography (PET) imaging ligands as potential cancer imaging probes. We will test the hypothesis that TSPO ligands can be developed and optimized for cancer imaging studies. We anticipate that these studies will lay the framework for future advancement of the most promising novel TSPO ligands to the clinic for cancer imaging studies in patients.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA163806-04
Application #
8881115
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Tandon, Pushpa
Project Start
2012-09-01
Project End
2016-04-29
Budget Start
2015-07-01
Budget End
2016-04-29
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37240

  Publications

Tantawy, Mohammed N; Charles Manning, H; Peterson, Todd E et al. (2018) Translocator Protein PET Imaging in a Preclinical Prostate Cancer Model. Mol Imaging Biol 20:200-204
Tang, Dewei; Li, Jun; Buck, Jason R et al. (2017) Evaluation of TSPO PET Ligands [18F]VUIIS1009A and [18F]VUIIS1009B: Tracers for Cancer Imaging. Mol Imaging Biol 19:578-588
Li, Jun; Smith, Jarrod A; Dawson, Eric S et al. (2017) Optimized Translocator Protein Ligand for Optical Molecular Imaging and Screening. Bioconjug Chem 28:1016-1023
Li, Jun; Schulte, Michael L; Nickels, Michael L et al. (2016) New structure-activity relationships of N-acetamide substituted pyrazolopyrimidines as pharmacological ligands of TSPO. Bioorg Med Chem Lett 26:3472-7
Manning, H Charles; Buck, Jason R; Cook, Rebecca S (2016) Mouse Models of Breast Cancer: Platforms for Discovering Precision Imaging Diagnostics and Future Cancer Medicine. J Nucl Med 57 Suppl 1:60S-8S
Buck, Jason R; McKinley, Eliot T; Fu, Allie et al. (2015) Preclinical TSPO Ligand PET to Visualize Human Glioma Xenotransplants: A Preliminary Study. PLoS One 10:e0141659
Powell, Anne E; Vlacich, Gregory; Zhao, Zhen-Yang et al. (2014) Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis. Am J Physiol Gastrointest Liver Physiol 307:G16-23
Tang, Dewei; Nickels, Michael L; Tantawy, M Noor et al. (2014) Preclinical imaging evaluation of novel TSPO-PET ligand 2-(5,7-Diethyl-2-(4-(2-[(18)F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([ (18)F]VUIIS1008) in glioma. Mol Imaging Biol 16:813-20
Cheung, Yiu-Yin; Nickels, Michael L; Tang, Dewei et al. (2014) 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-4H-pyridazino[4,5-b]indole-1-acetamide, a potent pyridazinoindole ligand for PET imaging of TSPO in cancer. Bioorg Med Chem Lett 24:4466-4471
Tang, Dewei; McKinley, Eliot T; Hight, Matthew R et al. (2013) Synthesis and structure-activity relationships of 5,6,7-substituted pyrazolopyrimidines: discovery of a novel TSPO PET ligand for cancer imaging. J Med Chem 56:3429-33

Showing the most recent 10 out of 13 publications