Detection of Active Caspase-3 in Mouse Models of Stroke and Alzheimer's Disease with a Novel Dual Positron Emission Tomography/Fluorescent Tracer [68Ga]Ga-TC3-OGDOTA

Valeriy G Ostapchenko; Jonatan Snir; Mojmir Suchy; Jue Fan; M Rebecca Cobb; Blaine A Chronik; Michael Kovacs; Vania F Prado; Robert H E Hudson; Stephen H Pasternak; Marco A M Prado; Robert Bartha

doi:10.1155/2019/6403274

Detection of Active Caspase-3 in Mouse Models of Stroke and Alzheimer's Disease with a Novel Dual Positron Emission Tomography/Fluorescent Tracer [⁶⁸Ga]Ga-TC3-OGDOTA

Contrast Media Mol Imaging. 2019 Jan 14:2019:6403274. doi: 10.1155/2019/6403274. eCollection 2019.

Authors

Valeriy G Ostapchenko¹, Jonatan Snir^{1

2}, Mojmir Suchy^{1

3}, Jue Fan¹, M Rebecca Cobb^{1

4}, Blaine A Chronik^{2

5}, Michael Kovacs^{2

6}, Vania F Prado^{1

7

8}, Robert H E Hudson³, Stephen H Pasternak^{1

9}, Marco A M Prado^{1

7

8}, Robert Bartha^{1

2}

Affiliations

¹ Robarts Research Institute, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5B7.
² Department of Medical Biophysics, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5B7.
³ Department of Chemistry, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5B7.
⁴ Neuroscience Program, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5B7.
⁵ Department of Physics and Astronomy, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5B7.
⁶ Lawson Health Research Institute, 268 Grosvenor Street, London, ON, Canada N6A 4V2.
⁷ Department of Physiology and Pharmacology, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5B7.
⁸ Department of Anatomy and Cell Biology, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5B7.
⁹ Department of Clinical Neurological Sciences, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5B7.

Abstract

Apoptosis is a feature of stroke and Alzheimer's disease (AD), yet there is no accepted method to detect or follow apoptosis in the brain in vivo. We developed a bifunctional tracer [⁶⁸Ga]Ga-TC3-OGDOTA containing a cell-penetrating peptide separated from fluorescent Oregon Green and ⁶⁸Ga-bound labels by the caspase-3 recognition peptide DEVD. We hypothesized that this design would allow [⁶⁸Ga]Ga-TC3-OGDOTA to accumulate in apoptotic cells. In vitro, Ga-TC3-OGDOTA labeled apoptotic neurons following exposure to camptothecin, oxygen-glucose deprivation, and β-amyloid oligomers. In vivo, PET showed accumulation of [⁶⁸Ga]Ga-TC3-OGDOTA in the brain of mouse models of stroke or AD. Optical clearing revealed colocalization of [⁶⁸Ga]Ga-TC3-OGDOTA and cleaved caspase-3 in brain cells. In stroke, [⁶⁸Ga]Ga-TC3-OGDOTA accumulated in neurons in the penumbra area, whereas in AD mice [⁶⁸Ga]Ga-TC3-OGDOTA was found in single cells in the forebrain and diffusely around amyloid plaques. In summary, this bifunctional tracer is selectively associated with apoptotic cells in vitro and in vivo in brain disease models and represents a novel tool for apoptosis detection that can be used in neurodegenerative diseases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / diagnostic imaging*
Animals
Caspase 3 / metabolism*
Cells, Cultured
Female
Gallium Radioisotopes / chemistry*
Kinetics
Male
Mice
Microscopy, Confocal
Positron-Emission Tomography / methods*
Stroke / diagnostic imaging*

Substances

Gallium Radioisotopes
Caspase 3

Abstract

Publication types

MeSH terms

Substances

Grants and funding