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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA163806-03
Application #
8686781
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Tandon, Pushpa
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Nashville
State
TN
Country
United States
Zip Code
37212
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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
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
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 24:4466-71
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
Thompson, Misty M; Manning, H Charles; Ellacott, Kate L J (2013) Translocator protein 18 kDa (TSPO) is regulated in white and brown adipose tissue by obesity. PLoS One 8:e79980
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
Tang, Dewei; Hight, Matthew R; McKinley, Eliot T et al. (2012) Quantitative preclinical imaging of TSPO expression in glioma using N,N-diethyl-2-(2-(4-(2-18F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide. J Nucl Med 53:287-94