Abstract
BackgroundCD13 is selectively upregulated in angiogenic active endothelium and can serve as a target for molecular imaging tracers to non-invasively visualise angiogenesis in vivo. Non-invasive determination of CD13 expression can potentially be used to monitor treatment response to pro-angiogenic drugs in ischemic heart disease. CD13 binds peptides and proteins through binding to tripeptide asparagine-glycine-arginine (NGR) amino acid residues.Previous studies using in vivo fluorescence microscopy and magnetic resonance imaging indicated that cNGR tripeptide-based tracers specifically bind to CD13 in angiogenic vasculature at the border zone of the infarcted myocardium.In this study, the CD13-binding characteristics of an 111In-labelled cyclic NGR peptide (cNGR) were determined. To increase sensitivity, we visualised 111In-DTPA-cNGR in combination with 99mTc-sestamibi using dual-isotope SPECT to localise CD13 expression in perfusion-deficient regions.MethodsMyocardial infarction (MI) was induced in Swiss mice by ligation of the left anterior descending coronary artery (LAD). 111In-DTPA-cNGR and 99mTc-sestamibi dual-isotope SPECT imaging was performed 7 days post-ligation in MI mice and in control mice. In addition, ex vivo SPECT imaging on excised hearts was performed, and biodistribution of 111In-DTPA-cNGR was determined using gamma counting. Binding specificity of 111In-DTPA-cNGR to angiogenic active endothelium was determined using the Matrigel model.ResultsLabelling yield of 111In-DTPA-cNGR was 95% to 98% and did not require further purification. In vivo, 111In-DTPA-cNGR imaging showed a rapid clearance from non-infarcted tissue and a urinary excretion of 82% of the injected dose (I.D.) 2 h after intravenous injection in the MI mice. Specific binding of 111In-DTPA-cNGR was confirmed in the Matrigel model and, moreover, binding was demonstrated in the infarcted myocardium and infarct border zone.ConclusionsOur newly designed and developed angiogenesis imaging probe 111In-DTPA-cNGR allows simultaneous imaging of CD13 expression and perfusion in the infarcted myocardium and the infarct border zone by dual-isotope micro-SPECT imaging.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0081-7) contains supplementary material, which is available to authorized users.
Highlights
CD13 is selectively upregulated in angiogenic active endothelium and can serve as a target for molecular imaging tracers to non-invasively visualise angiogenesis in vivo
Reaction progress was monitored by analytical HPLC, and after reaction completion, oxidised NAc-CysAsn-Gly-Arg-Cys-Gly-Gly-Lys-NH2 was purified by semipreparative HPLC
Chemistry After cleavage from the solid support with HF, the linear NGR peptide was cyclised by the formation of an internal disulfide bond
Summary
CD13 is selectively upregulated in angiogenic active endothelium and can serve as a target for molecular imaging tracers to non-invasively visualise angiogenesis in vivo. Non-invasive determination of CD13 expression can potentially be used to monitor treatment response to pro-angiogenic drugs in ischemic heart disease. Previous studies using in vivo fluorescence microscopy and magnetic resonance imaging indicated that cNGR tripeptide-based tracers bind to CD13 in angiogenic vasculature at the border zone of the infarcted myocardium. The formation of new capillaries from existing micro vessels occurs as a natural healing process following myocardial infarction (MI) [1]. This process, called angiogenesis, is triggered by ischemia and results in partial restoration of blood perfusion in the ischemic zone. The clinical translation of these therapies has proven to be difficult, and the clinical benefit for MI patients has been disappointing and controversial [6,7,8,9,10,11,12]
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