PET imaging of angiogenesis after myocardial infarction/reperfusion using a one-step labeled integrin-targeted tracer 18F-AlF-NOTA-PRGD2

Abstract

Objective The αvβ3 integrin represents a potential target for noninvasive imaging of angiogenesis. The purpose of this study was to evaluate a novel one-step labeled integrin αvβ3 targeting PET probe, 18F-AlF-NOTA-PRGD2, for angiogenesis imaging in a myocardial infract/reperfusion (MI/R) animal model. Methods Male SD rats underwent 45 min transient left coronary artery occlusion followed by reperfusion. The myocardial infarction was confirmed by ECG, 18F-FDG imaging and cardiac ultrasound. In vivo PET imaging were used to determine myocardial uptake of 18F-AlF-NOTA-PRGD2 at different time points following reperfusion. The control peptide RAD was labeled with a similar procedure and used to confirm the specificity. Ex vivo autoradiographic analysis and CD31/CD61 double immunofluoresence staining were performed to validate the PET results. Results Myocardial origin of the 18F-AlF-NOTA-PRGD2 accumulation was confirmed by 18F-FDG and autoradiography. PET imaging demonstrated increased focal accumulation of 18F-AlF-NOTA-PRGD2 in the infarcted area started at day 3 (0.28 ± 0.03 %ID/g, p < 0.05), peaked between 1 and 3 weeks (0.59 ± 0.16 and 0.55 ± 0.13 %ID/g, respectively). The focal accumulation decreased but still kept at a higher level than the sham group after 4 months of reperfusion (0.31 ± 0.01 %ID/g, p < 0.05). Pretreatment with unlabeled RGD peptide significantly decreased tracer uptake, indicating integrin specificity of this tracer. At 1 week after MI/R, uptake of the control tracer 18F-AlF-NOTA-RAD that does not bind to integrin, in the infarcted area, was only 0.21 ± 0.01 %ID/g. Autoradiographic imaging showed the same trend of uptake in myocardial infarction area. The time course of focal tracer uptake was consistent with the pattern of vascular density and integrin β3 expression as measured by CD31 and CD61 immunostaining analysis. Conclusion PET imaging using one-step labeled 18F-AlF-NOTA-PRGD2 allows noninvasive visualization of ischemia-reperfusion induced myocardial angiogenesis longitudinally. The favorable in vivo kinetics and easy production method of this integrin targeted PET tracer facilitates its future clinical translation for lesion evaluation and therapy response monitoring in patients with occlusive cardiovascular diseases.

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

“…SSTR2-targeted radiotherapeutics that use lutetium-177 and yttrium-90 are also currently under evaluation 192,193 . Other notable targeted imaging agents in clinical trials include: 111 In-exendin-4, which targets glucagon-like peptide 1 receptor and is being tested for imaging insulinomas (NCT02127541 and NCT00937079) 194 ; NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid)-(PEGylated arginine-glycine-aspartic acid dimer) PRGD2 and fluciclatide, which target α v β 3 integrin and are being tested in lung cancer (NCT01527058) [195][196][197][198][199][200] ; 18 F-VM4-037, an imaging agent that has completed Phase II trials in kidney cancer (NCT01712685) and targets carbonic anhydrase 9, which is overexpressed in hypoxic tumours; and BAY86-7548, a 68 Ga- …”

PET of Glucagonlike Peptide Receptor Upregulation After Myocardial Ischemia or Reperfusion Injury

“…In a previous study, we performed longitudinal PET using 18 F-AlF-NOTA-PRGD2 to monitor quantitatively integrin a v b 3 changes after MI/R (39). Focal accumulation of 18 F-AlF-NOTA-RGD2 in the infarct area started at day 3 and reached a plateau between 1 and 3 wk.…”

First 18F-labeled ligand for PET imaging of uPAR: In vivo studies in human prostate cancer xenografts

“…In this method, the traditional critical azeotropic drying step for 18 F-fluoride is not necessary, and the labeling can be performed in water. A number of recently published studies have illustrated the potential of this new 18 F-labeling method, where successful labeling of ligands for PET imaging of angiogenesis [19,20], Bombesin [21], EGFR [22] and hypoxia [23] have been demonstrated.…”