Abstract
BackgroundExpression of αvβ3 integrin is increased after myocardial infarction as part of the repair process. Increased expression of αvβ3 has been shown by molecular imaging with 18F-galacto-RGD in a rat model. The 68Ga-labelled RGD compounds 68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 have high specificity and affinity, and may therefore serve as alternatives of 18F-galacto-RGD for integrin imaging.MethodsLeft coronary artery ligation was performed in rats. After 1 week, rats were imaged with [13N]NH3, followed by 18F-galacto-RGD, 68Ga-NODAGA-RGD or 68Ga-TRAP(RGD)3 using a dedicated animal PET/CT device. Rats were killed, and the activity in tissues was measured by gamma counting. The heart was sectioned for autoradiography and histology. Immunohistochemistry was performed on consecutive sections using CD31 for the endothelial cells and CD61 for β3 expression (as part of the αvβ3 receptor).ResultsIn vivo imaging showed focal RGD uptake in the hypoperfused area of infarcted myocardium as defined with [13N]NH3 scan. In autoradiography images, augmented uptake of all RGD tracers was observed within the infarct area as verified by the HE staining. The tracer uptake ratios (infarct vs. remote) were 4.7 ± 0.8 for 18F-galacto-RGD, 5.2 ± 0.8 for 68Ga-NODAGA-RGD, and 4.1 ± 0.7 for 68Ga-TRAP(RGD)3. The 68Ga-NODAGA-RGD ratio was higher compared to 68Ga-TRAP(RGD)3 (p = 0.04), but neither of the 68Ga tracers differed from 18F-galacto-RGD (p > 0.05). The area of augmented 68Ga-RGD uptake was associated with β3 integrin expression (CD61).Conclusion68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 uptake was equally increased in the infarct area at 1 week post infarction as 18F-galacto-RGD. These results show the potential of 68Ga-labelled RGD peptides to monitor integrin expression as a part of myocardial repair and angiogenesis after ischaemic injury in vivo.
Highlights
Expression of αvβ3 integrin is increased after myocardial infarction as part of the repair process
Alternative RGD compounds have been sought after, such as a one-step-labelled positronemission tomography (PET) tracer,18F-AIF-NOTA-PRGD2, which was found to reflect ischaemia-induced angiogenesis in a rat model [7].68Ga-NODAGA-cyclo(RGDyK) and 68Ga-TRAP(cyclo(RGDfK))3 have been evaluated for αvβ3 imaging in tumour models, showing high target-to -background ratios [9,10,11,12]. 68Ga tracers have the advantage of easy and fast production with a generator-produced radionuclide. 68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 can be produced with high specific activity (approximately 200 to 600 GBq/μmol for 68Ga-NODAGA-RGD and over 5 TBq/μmol for 68GaTRAP(RGD)3 [9,11]), which is essential when using 68Ga-labelled peptides, especially in case of small animal studies
Animal model Ligation of the left anterior descending (LAD) resulted in a myocardial infarction, which covered 15% to 25% of myocardial axial plain, as measured from autoradiography sections
Summary
Expression of αvβ integrin is increased after myocardial infarction as part of the repair process. The 68Ga-labelled RGD compounds 68Ga-NODAGA-RGD and 68Ga-TRAP(RGD) have high specificity and affinity, and may serve as alternatives of 18F-galacto-RGD for integrin imaging. Taken together, imaging of αvβ integrin expression is an attractive tool to assay the post-MI angiogenesis and may be potentially used to predict outcome of infarct healing. Alternative RGD compounds have been sought after, such as a one-step-labelled positronemission tomography (PET) tracer,18F-AIF-NOTA-PRGD2, which was found to reflect ischaemia-induced angiogenesis in a rat model [7].68Ga-NODAGA-cyclo(RGDyK) and 68Ga-TRAP(cyclo(RGDfK)) have been evaluated for αvβ imaging in tumour models, showing high target-to -background ratios [9,10,11,12]. Alternative RGD compounds have been sought after, such as a one-step-labelled positronemission tomography (PET) tracer,18F-AIF-NOTA-PRGD2, which was found to reflect ischaemia-induced angiogenesis in a rat model [7].68Ga-NODAGA-cyclo(RGDyK) and 68Ga-TRAP(cyclo(RGDfK)) have been evaluated for αvβ imaging in tumour models, showing high target-to -background ratios [9,10,11,12]. 68Ga tracers have the advantage of easy and fast production with a generator-produced radionuclide. 68Ga-NODAGA-RGD and 68Ga-TRAP(RGD) can be produced with high specific activity (approximately 200 to 600 GBq/μmol for 68Ga-NODAGA-RGD and over 5 TBq/μmol for 68GaTRAP(RGD)3 [9,11]), which is essential when using 68Ga-labelled peptides, especially in case of small animal studies
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