Kiran Gona1,2, Jakub Toczek1,2, Yunpeng Ye1,2, Nowshin Sanzida1,2, Arvene Golbazi1,2, Parnaz Boodagh1,2, Mani Salarian1,2, Jae-Joon Jung1,2, Saranya Rajendran1,2, Gunjan Kukreja1,2, Terence L Wu3, Laurent Devel4, Mehran M Sadeghi1,2. 1. Cardiovascular Molecular Imaging Laboratory, Section of Cardiovascular Medicine and Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut 06511, United States. 2. Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516, United States. 3. Yale West Campus Analytical Core, Yale University, West Haven, Connecticut 06516, United States. 4. CEA, INRAE, Medicaments et Technologies pour la Sante (MTS), SIMoS, Université Paris-Saclay, 91191 Gif-sur-Yvette, France.
Abstract
Macrophage elastase [matrix metalloproteinase (MMP)-12] is the most upregulated MMP in abdominal aortic aneurysm (AAA) and, hence, MMP-12-targeted imaging may predict AAA progression and rupture risk. Here, we report the design, synthesis, and evaluation of three novel hydroxamate-based selective MMP-12 inhibitors (CGA, CGA-1, and AGA) and the methodology to obtain MMP-12 selectivity from hydroxamate-based panMMP inhibitors. Also, we report two 99mTc-radiotracers, 99mTc-AGA-1 and 99mTc-AGA-2, derived from AGA. 99mTc-AGA-2 displayed faster blood clearance in mice and better radiochemical stability compared to 99mTc-AGA-1. Based on this, 99mTc-AGA-2 was chosen as the lead tracer and tested in murine AAA. 99mTc-AGA-2 uptake detected by autoradiography was significantly higher in AAA compared to normal aortic regions. Specific binding of the tracer to MMP-12 was demonstrated through ex vivo competition. Accordingly, this study introduces a novel family of selective MMP-12 inhibitors and tracers, paving the way for further development of these agents as therapeutic and imaging agents.
Macrophage elastase [n class="Gene">matrix metalloproteinase (MMP)-12] is the most upregulated MMP in abdominal aortic aneurysm (AAA) and, hence, MMP-12-targeted imaging may predict AAA progression and rupture risk. Here, we report the design, synthesis, and evaluation of three novel hydroxamate-based selective MMP-12 inhibitors (CGA, CGA-1, and AGA) and the methodology to obtain MMP-12 selectivity from hydroxamate-based panMMP inhibitors. Also, we report two 99mTc-radiotracers, 99mTc-AGA-1 and 99mTc-AGA-2, derived from AGA. 99mTc-AGA-2 displayed faster blood clearance in mice and better radiochemical stability compared to 99mTc-AGA-1. Based on this, 99mTc-AGA-2 was chosen as the lead tracer and tested in murineAAA. 99mTc-AGA-2 uptake detected by autoradiography was significantly higher in AAA compared to normal aortic regions. Specific binding of the tracer to MMP-12 was demonstrated through ex vivo competition. Accordingly, this study introduces a novel family of selective MMP-12 inhibitors and tracers, paving the way for further development of these agents as therapeutic and imaging agents.
Authors: M Yamamoto; R Hirayama; K Naruse; K Yoshino; A Shimada; S Inoue; N Kayagaki; H Yagita; K Okumura; S Ikeda Journal: Drug Des Discov Date: 1999-08
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Authors: Péter Bencsik; Krisztina Kupai; Anikó Görbe; Éva Kenyeres; Zoltán V Varga; János Pálóczi; Renáta Gáspár; László Kovács; Lutz Weber; Ferenc Takács; István Hajdú; Gabriella Fabó; Sándor Cseh; László Barna; Tamás Csont; Csaba Csonka; György Dormán; Péter Ferdinandy Journal: Front Pharmacol Date: 2018-04-05 Impact factor: 5.810