An Aspartyl Cathepsin Targeted PET Agent: Application in an Alzheimer’s Disease Mouse Model

Article type: Research Article

Authors: Snir, Jonatan A.^{a; b} | Suchy, Mojmir^{b; c} | Bindseil, Geron A.^d | Kovacs, Michael^{a; e} | Chronik, Blaine A.^{b; d} | Hudson, Robert H.E.^c | Pasternak, Stephen H.^{e; f} | Bartha, Robert^{a; b; *}

Affiliations: [a] Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada | [b] Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, London, ON, Canada | [c] Department of Chemistry, University of Western Ontario, London, ON, Canada | [d] Department of Physics and Astronomy, University of Western Ontario, London, ON, Canada | [e] Lawson Health Research Institute, London, ON, Canada | [f] J. Allyn Taylor Centre for Cell Biology, Molecular Brain Research Group, Robarts Research Institute, University of Western Ontario, London, ON, Canada | [g] Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada

Correspondence: [*] Correspondence to: Dr. Robert Bartha, PhD, Centre for Functional and Metabolic Mapping, Robarts Research Institute, University of Western Ontario, 1151 Richmond Street, London, ON N6A 3K7 Canada. Tel.: +1 519 931 5777/Ext. 24039; Fax.: +1 519 931 5224; E-mail: [email protected].

Abstract: Background:Early detection of Alzheimer’s disease (AD) pathology is a serious challenge for both diagnosis and clinical trials. The aspartyl protease, Cathepsin D (CatD), is overexpressed in AD and could be a biomarker of disease. We have previously designed a unique contrast agent (CA) for dual-optical and magnetic resonance imaging of the activity of the CatD class of enzymes. Objective:To compare the uptake and retention of a novel, more sensitive, and clinically-translatable 68Ga PET tracer targeting CatD activity in 5XFAD mice and non-Tg littermates. Methods:The targeted CA consisted of an HIV-1 Tat cell penetrating peptide (CPP) conjugated to a specialized cleavage sequence targeting aspartyl cathepsins and a DOTA conjugate chelating 68Ga. PET images were acquired using a Siemens Inveon preclinical microPET in female Tg AD mice and non-Tg age matched female littermates (n = 5–8) following intravenous CA administration at 2, 6, and 9 months of age. Additionally, 18F fluorodeoxyglucose (FDG) PET imaging was performed at 10 months to measure glucose uptake. Results:The Tg mice showed significantly higher relative uptake rate of the targeting CA in the forebrain relative to hindbrain at all ages compared to controls, consistent with histology. In contrast, no differences were seen in CA uptake in other organs. Additionally, the Tg mice did not show any differences in relative uptake of FDG at 10 months of age in the forebrain relative to the hindbrain compared to age matched non-Tg controls. Conclusions:Elevated aspartryl cathepsin activity was detected in vivo in the 5XFAD mouse model of AD using a novel targeted PET contrast agent.

Keywords: Alzheimer’s disease, cathepsin D, mice, molecular imaging, radionuclide imaging

DOI: 10.3233/JAD-170115

Journal: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1241-1252, 2018