{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T22:11:09Z","timestamp":1768083069393,"version":"3.49.0"},"reference-count":54,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2012,11,21]],"date-time":"2012-11-21T00:00:00Z","timestamp":1353456000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Contrast Media &amp; Molecular"],"published-print":{"date-parts":[[2013,3]]},"abstract":"<jats:p>Currently there are no approved biomarkers for the pre\u2010symptomatic diagnosis of Alzheimer's disease (AD). Cathepsin\u2010D (Cat\u2010D) is a lysosomal protease that is present at elevated levels in amyloid plaques and neurons in patients with AD and is also elevated in some cancers. We have developed a magnetic resonance imaging (MRI)\/fluorescent contrast agent to detect Cat\u2010D enzymatic activity. The purpose of this study was to investigate the cellular and tissue uptake of this MRI\/fluorescent contrast agent. The agent consists of an MRI probe [DOTA\u2013caged metal ion (Gd<jats:sup>3+<\/jats:sup>or Tm<jats:sup>3+<\/jats:sup>)] and a fluorescent probe coupled to a cell\u2010penetrating\u2010peptide sequence by a Cat\u2010D recognition site. The relaxivity of Gd<jats:sup>3+<\/jats:sup>\u2013DOTA\u2013CAT<jats:sub>(cleaved)<\/jats:sub>was measured in 10% heat\u2010treated bovine serum albumin (BSA) phantoms to assess contrast efficacy at magnetic fields ranging from 0.24 mT to 9.4\u2009T.<jats:italic>In vitro<\/jats:italic>, Tm<jats:sup>3+<\/jats:sup>\u2013DOTA\u2013CAT was added to neuronal SN56 cells over\u2010expressing Cat\u2010D and live\u2010cell confocal microscropy was performed at 30\u2009min. Tm<jats:sup>3+<\/jats:sup>\u2013DOTA\u2013CAT was also intravenously injected into APP\/PS1\u2010dE9 Alzheimer's disease mice (<jats:italic>n\u2009=<\/jats:italic>\u20099) and controls (<jats:italic>n\u2009=<\/jats:italic>\u20098). Cortical and hippocampal uptake was quantified at 30, 60 and 120\u2009min post\u2010injection using confocal microscopy. The liver and kidneys were also evaluated for contrast agent uptake. The relaxivity of Gd<jats:sup>3+<\/jats:sup>\u2013DOTA\u2013CAT<jats:sub>(cleaved)<\/jats:sub>was 3.3 (mM\u2009s)<jats:sup>\u22121<\/jats:sup>in 10% BSA at 9.4\u2009T.<jats:italic>In vitro<\/jats:italic>, cells over\u2010expressing Cat\u2010D preferentially took up the contrast agent in a concentration\u2010dependent manner.<jats:italic>In vivo<\/jats:italic>, the contrast agent effectively crossed the blood\u2013brain barrier and exhibited a distinct time course of uptake and retention in APP\/PS1\u2010dE9 transgenic mice compared with age\u2010matched controls. At clinical and high magnetic field strengths, Gd<jats:sup>3+<\/jats:sup>\u2013DOTA\u2013CAT produced greater<jats:italic>T<\/jats:italic><jats:sub>1<\/jats:sub>relaxivity than Gd<jats:sup>3+<\/jats:sup>\u2013DTPA. Tm<jats:sup>3+<\/jats:sup>\u2013DOTA\u2013CAT was taken up in a dose\u2010dependent manner in cells over\u2010expressing Cathepsin\u2010D and was shown to transit the blood\u2013brain barrier<jats:italic>in vivo<\/jats:italic>. This strategy may be useful for the<jats:italic>in vivo<\/jats:italic>detection of enzyme activity and for the diagnosis of Alzheimer's disease. Copyright \u00a9 2012 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/cmmi.1502","type":"journal-article","created":{"date-parts":[[2012,12,11]],"date-time":"2012-12-11T19:52:29Z","timestamp":1355255549000},"page":"127-139","source":"Crossref","is-referenced-by-count":17,"title":["A dual magnetic resonance imaging\/fluorescent contrast agent for Cathepsin\u2010D detection"],"prefix":"10.1002","volume":"8","author":[{"given":"Robert","family":"Ta","sequence":"first","affiliation":[{"name":"Imaging Research Group, Robarts Research Institute The University of Western Ontario London Ontario Canada"},{"name":"Department of Medical Biophysics The University of Western Ontario London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mojmir","family":"Suchy","sequence":"additional","affiliation":[{"name":"Imaging Research Group, Robarts Research Institute The University of Western Ontario London Ontario Canada"},{"name":"Department of Chemistry The University of Western Ontario London Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua H.K.","family":"Tam","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology The University of Western Ontario London Ontario Canada"},{"name":"J. 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