title: Molecular imaging of angiogenesis after myocardial infarction by (111)In-DTPA-cNGR and (99m)Tc-sestamibi dual-isotope myocardial SPECT.
abstract: BACKGROUND
  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. 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 (111)In-labelled cyclic NGR peptide (cNGR) were determined. To increase sensitivity, we visualised (111)In-DTPA-cNGR in combination with (99m)Tc-sestamibi using dual-isotope SPECT to localise CD13 expression in perfusion-deficient regions.
  
  
  METHODS
  Myocardial infarction (MI) was induced in Swiss mice by ligation of the left anterior descending coronary artery (LAD). (111)In-DTPA-cNGR and (99m)Tc-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 (111)In-DTPA-cNGR was determined using gamma counting. Binding specificity of (111)In-DTPA-cNGR to angiogenic active endothelium was determined using the Matrigel model.
  
  
  RESULTS
  Labelling yield of (111)In-DTPA-cNGR was 95% to 98% and did not require further purification. In vivo, (111)In-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 (111)In-DTPA-cNGR was confirmed in the Matrigel model and, moreover, binding was demonstrated in the infarcted myocardium and infarct border zone.
  
  
  CONCLUSIONS
  Our newly designed and developed angiogenesis imaging probe (111)In-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.
authors: Department of Nuclear Medicine, Maastricht University Medical Centre (MUMC+), Postbox 5800, 6202 AZ Maastricht, The Netherlands ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors: Geert
authors: G
authors: Hendrikx
authors: Department of Nuclear Medicine, Maastricht University Medical Centre (MUMC+), Postbox 5800, 6202 AZ Maastricht, The Netherlands ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors: Marijke
authors: M
authors: De Saint-Hubert
authors: Department of Biochemistry, Maastricht University, Maastricht, The Netherlands ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors: Ingrid
authors: I
authors: Dijkgraaf
authors: Department of Nuclear Medicine, Maastricht University Medical Centre (MUMC+), Postbox 5800, 6202 AZ Maastricht, The Netherlands.
authors: Matthias
authors: M
authors: Bauwens
authors: Department of Nuclear Medicine, Maastricht University Medical Centre (MUMC+), Postbox 5800, 6202 AZ Maastricht, The Netherlands ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors: Kim
authors: K
authors: Douma
authors: Department of Nuclear Medicine, Maastricht University Medical Centre (MUMC+), Postbox 5800, 6202 AZ Maastricht, The Netherlands.
authors: Roel
authors: R
authors: Wierts
authors: Department of Nuclear Medicine, Maastricht University Medical Centre (MUMC+), Postbox 5800, 6202 AZ Maastricht, The Netherlands.
authors: Ivo
authors: I
authors: Pooters
authors: Department of Physiology, CARIM, Maastricht University, Maastricht, The Netherlands ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors: Nynke Ms
authors: NM
authors: Van den Akker
authors: Department of Biochemistry, Maastricht University, Maastricht, The Netherlands ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors: Tilman M
authors: TM
authors: Hackeng
authors: Department of Physiology, CARIM, Maastricht University, Maastricht, The Netherlands ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors: Mark J
authors: MJ
authors: Post
authors: Department of Nuclear Medicine, Maastricht University Medical Centre (MUMC+), Postbox 5800, 6202 AZ Maastricht, The Netherlands ; Department of Nuclear Medicine, University hospital, RWTH University, Aachen, Germany.
authors: Felix M
authors: FM
authors: Mottaghy
keywords: Angiogenesis; CD13; Micro-SPECT; Myocardial infarction