This application requests funds to support a mentored Research Career Development Award ("K" series, CDA) for a candidate at Vanderbilt University. The candidate has formal training in chemistry and imaging sciences, and seeks to become an independent investigator within the field of molecular imaging. Funds to support this application will facilitate critical training in cancer biology, high-throughput screening, and mass spectrometry. A career development plan has been established that includes didactic training, laboratory training, and a research plan that ensures future success as an independent investigator. The proposed research seeks to develop quantitative, high-throughput screening (HTS) technology to accelerate the discovery and development of small molecule molecular imaging agents (MIAs). Ml is an emerging research tool and clinical discipline that aims to non-invasively characterize in vivo molecular processes at the cellular and sub-cellular levels. Currently, the MIA development paradigm is costly, time consuming, and narrow in scope. Given that genomic and proteomic technologies are now being used to rapidly discover novel molecular targets, there is a pressing need to develop new approaches which will accelerate the MIA discovery process. Here, we propose a library-based, HT approach that will enable the discovery of lead compounds with specificity for unique cellular phenotypes. Our approach will be universally applicable to numerous cell-based systems and facilitate quantification of compound uptake without the use of markers or labels. We will validate our methodology by screening for compounds able to selectively label various cell types found within the chronic inflammatory microenvironment of tumors. Under these proposed investigations, cellular-specific small molecules will be discovered in vitro and validated in vivo, with optimal candidates selected for future development as imaging agents. We will meet these goals by synergizing a small molecule HT screen with MALDI-QqTOF-MS according to the following specific aims:
AIM 1 - Develop a quantitative, HT method for screening cellular uptake of library-based small molecules.
AIM 2 - Identify small molecules from the HTS that will discriminate type-1, pro-inflammatory macrophages from type-2, anti-inflammatory macrophages and tumor cells.
AIM 3 - Validate the cellular specificity of lead compounds in vivo. Relevance to public health: In vivo molecular imaging agents are capable of measuring discrete, biological events associated with diseases such as cancer. The goal of this proposed CDA and research is to realize improved molecular imaging agents for translational research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Quantitative Research Career Development Award (K25)
Project #
5K25CA127349-05
Application #
8239453
Study Section
Subcommittee G - Education (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$141,858
Indirect Cost
$10,508
Name
Vanderbilt University Medical Center
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Schulte, Michael L; Khodadadi, Alexandra B; Cuthbertson, Madison L et al. (2016) 2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids: A novel scaffold for inhibition of ASCT2-mediated glutamine transport. Bioorg Med Chem Lett 26:1044-7
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
McKinley, Eliot T; Watchmaker, Jennifer M; Chakravarthy, A Bapsi et al. (2015) [(18)F]-FLT PET to predict early response to neoadjuvant therapy in KRAS wild-type rectal cancer: a pilot study. Ann Nucl Med 29:535-42
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
Hight, Matthew R; Cheung, Yiu-Yin; Nickels, Michael L et al. (2014) A peptide-based positron emission tomography probe for in vivo detection of caspase activity in apoptotic cells. Clin Cancer Res 20:2126-35
McKinley, Eliot T; Zhao, Ping; Coffey, Robert J et al. (2014) 3'-Deoxy-3'-[18F]-Fluorothymidine PET imaging reflects PI3K-mTOR-mediated pro-survival response to targeted therapy in colorectal cancer. PLoS One 9:e108193
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
Uddin, Md Imam; Buck, Jason R; Schulte, Michael L et al. (2014) Microwave-assisted, one-pot reaction of 7-azaindoles and aldehydes: a facile route to novel di-7-azaindolylmethanes. Tetrahedron Lett 55:
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
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 38 publications