Non-invasive imaging is a powerful clinical tool for the early diagnosis, and monitoring of various disease processes. Next generation molecular imaging promises unparalleled opportunities for visualizing pulmonary infection and inflammation since molecular and cellular alterations occur earlier in a pathologic process, than structural changes. This rapidly developing technology has become an essential tool in the field of oncology, with similar potential for pulmonary infectious and inflammatory conditions. In a Mycobacterium tuberculosis infection model of macrophage-associated pulmonary inflammation, we have demonstrated that [125I]DPA-713, a novel imaging probe, accumulates in M. tuberculosis-induced inflammatory lesions in the lungs of infected mice. [125/4I]DPA-713 has several promising features as a pulmonary imaging agent: a) low molecular weight with excellent penetration into diseased tissues;b) specific mechanism-based tracer, targeting translocator protein (TSPO) in activated macrophages;c) can be labeled with different radioiodine isotopes (PET or SPECT) with short or long half-lives;d) excellent pharmacokinetic profile in lung tissues and;e) importantly, high target-to-non-target ratios for sensitive detectin of macrophage-associated pulmonary inflammation in pre-clinical models. Our central hypothesis is that iodo- DPA-713 is selectively retained by activated macrophages in pulmonary lesions and would therefore serve as a more specific imaging biomarker for real-time evaluation of macrophage-associated inflammation in lung tissues. We propose a multi-disciplinary collaboration, specifically responsive to this RFA for developing probes for activated macrophages and to develop software to process, quantify and correlate in vivo imaging data. We will focus on the following three objectives: 1) validate [125/4I]DPA-713-SPECT/ PET as a biomarker for serial monitoring of macrophage-associated pulmonary inflammation;2) perform toxicology studies and current Good Manufacturing Practice (cGMP) synthesis for iodo-DPA-713;3) develop and use computer-assisted image analysis tools for pulmonary disease. The overall goal is to have a fully validated probe ready for human administration and to file a FDA Investigational New Drug (IND) application at the end of the funding period. All tools developed in this proposal are directly translatable to humans, and will be broadly applicable to other macrophage-associated pulmonary infectious or inflammatory conditions.

Public Health Relevance

We propose a multi-disciplinary collaboration, for developing [125/4I]DPA-713-SPECT/ PET as a novel probe for in vivo imaging of activated macrophages in lung tissues, and to develop software to process, quantify and correlate in vivo imaging data. All tools developed in this proposal are directly translatable to humans, and will be applicable broadly to other macrophage-associated pulmonary infectious or inflammatory conditions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL116316-02
Application #
8550817
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (S1))
Program Officer
Lin, Sara
Project Start
2012-09-25
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$385,560
Indirect Cost
$147,560
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ordonez, Alvaro A; Weinstein, Edward A; Bambarger, Lauren E et al. (2016) A Systematic Approach for Developing Bacteria-Specific Imaging Tracers. J Nucl Med :
Ordonez, Alvaro A; Tasneen, Rokeya; Pokkali, Supriya et al. (2016) Mouse model of pulmonary cavitary tuberculosis and expression of matrix metalloproteinase-9. Dis Model Mech 9:779-88
Kübler, André; Luna, Brian; Larsson, Christer et al. (2015) Mycobacterium tuberculosis dysregulates MMP/TIMP balance to drive rapid cavitation and unrestrained bacterial proliferation. J Pathol 235:431-44
DeMarco, Vincent P; Ordonez, Alvaro A; Klunk, Mariah et al. (2015) Determination of [11C]rifampin pharmacokinetics within Mycobacterium tuberculosis-infected mice by using dynamic positron emission tomography bioimaging. Antimicrob Agents Chemother 59:5768-74
Salazar-Austin, Nicole; Ordonez, Alvaro A; Hsu, Alice Jenh et al. (2015) Extensively drug-resistant tuberculosis in a young child after travel to India. Lancet Infect Dis 15:1485-91
Ordonez, Alvaro A; DeMarco, Vincent P; Klunk, Mariah H et al. (2015) Imaging Chronic Tuberculous Lesions Using Sodium [(18)F]Fluoride Positron Emission Tomography in Mice. Mol Imaging Biol 17:609-14
Ordonez, Alvaro A; Pokkali, Supriya; DeMarco, Vincent P et al. (2015) Radioiodinated DPA-713 imaging correlates with bactericidal activity of tuberculosis treatments in mice. Antimicrob Agents Chemother 59:642-9
Xu, Ziyue; Bagci, Ulas; Jonsson, Colleen et al. (2014) Efficient ribcage segmentation from CT scans using shape features. Conf Proc IEEE Eng Med Biol Soc 2014:2899-902
Johnson, Daniel H; Via, Laura E; Kim, Peter et al. (2014) Nuclear imaging: a powerful novel approach for tuberculosis. Nucl Med Biol 41:777-84
Ziyue Xu; Bagci, Ulas; Jonsson, Colleen et al. (2014) Accurate and efficient separation of left and right lungs from 3D CT scans: A generic hysteresis approach. Conf Proc IEEE Eng Med Biol Soc 2014:6036-9

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