68Ga-NODAGA-RGDyK for αvβ3 integrin PET imaging

Buchegger, Franz; Viertl, David; Baechler, Sébastien; Dunet, Vincent; Kosinski, Marek; Poitry‐Yamate, Carole; Rüegg, Curzio; Prior, John O.

doi:10.3413/nukmed-0416-11-06

Cited by 18 publications

(12 citation statements)

References 18 publications

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“…Interestingly, these results confirm the validity of the extrapolation we previously made from mice biodistribution data to human dosimetry [24]. In that previous study, we had estimated human EDs being 12 μSv/MBq for male and 16 μSv/MBq for female, respectively.…”

Section: Discussionsupporting

confidence: 88%

“…In addition, this previous preclinical work included a tolerance test of NODAGA-RGDyK, showing no toxicity at 1000-fold excess per kilogram of body weight compared with the maximum amount of peptide injected in a 70-kg patient [24]. In the present study, we provide the first in-human dosimetry of 68 Ga-NODAGA-RGDyK in five male patients scheduled to undergo carotid endarterectomy.…”

Section: Discussionmentioning

confidence: 89%

“…As previously described [24], the NODAGA-RGDyK was radiolabelled with the 68 Ga eluate of a 68 Ge-generator IGC100 (Eckert & Ziegler, Germany) using an automatic processor unit, Modular-Lab PharmTracer (Eckert & Ziegler, Germany). 68 Ga was eluted with 0.1 mol/l HCl.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously reported preclinical dosimetry and toxicity results of 68 Ga-NODAGA-RGDyK in outbred female Hsd ICR (CD-1®) mice [24]. …”

Section: Introductionmentioning

confidence: 99%

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First in-human radiation dosimetry of 68Ga-NODAGA-RGDyK

et al. 2017

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BackgroundIntegrin-targeting radiopharmaceuticals have potential broad applications, spanning from cancer theranostics to cardiovascular diseases. We have previously reported preclinical dosimetry results of 68Ga-NODAGA-RGDyK in mice. This study presents the first human dosimetry of 68Ga-NODAGA-RGDyK in the five consecutive patients included in a clinical imaging protocol of carotid atherosclerotic plaques. Five male patients underwent whole-body time-of-flight (TOF) PET/CT scans 10, 60 and 120 min after tracer injection (200 MBq). Quantification of 68Ga activity concentration was first validated by a phantom study. To be used as input in OLINDA/EXM, time-activity curves were derived from manually drawn regions of interest over the following organs: brain, thyroid, lungs, heart, liver, spleen, stomach, kidneys, red marrow, pancreas, small intestine, colon, urinary bladder and whole body. A separate dosimetric analysis was performed for the choroid plexuses. Female dosimetry was extrapolated from male data. Effective doses (EDs) were estimated according to both ICRP60 and ICRP103 assuming 30-min and 1-h voiding cycles.ResultsThe body regions receiving the highest dose were urinary bladder, kidneys and choroid plexuses. For a 30-min voiding cycle, the EDs were 15.7 and 16.5 μSv/MBq according to ICRP60 and ICRP103, respectively. The extrapolation to female dosimetry resulted in organ absorbed doses 17% higher than those of male patients, on average.The 1-h voiding cycle extrapolation resulted in EDs of 19.3 and 19.8 μSv/MBq according to ICRP60 and ICRP103, respectively. A comparison is made with previous mouse dosimetry and with other human studies employing different RGD-based radiopharmaceuticals.ConclusionsAccording to ICRP60/ICRP103 recommendations, an injection of 200 MBq 68Ga-NODAGA-RGDyK leads to an ED in man of 3.86/3.92 mSv. For future therapeutic applications, specific attention should be directed to delivered dose to kidneys and potentially also to the choroid plexuses.Trial registrationClinical trial.gov, NCT01608516

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

“…We have previously reported preclinical dosimetry and toxicity results of 68 Ga-NODAGA-RGDyK in outbred female Hsd ICR (CD-1®) mice [24]. …”

Section: Introductionmentioning

confidence: 99%

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First in-human radiation dosimetry of 68Ga-NODAGA-RGDyK

et al. 2017

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“…The precursor can be obtained in Good Manufacturing Practices quality from a commercial supplier and the tracer is being developed for clinical use [26]. In addition to good target specificity, studies have indicated favorable kinetics, dosimetry and safety profile [27, 28]. In previous studies, [ 68 Ga]NODAGA-RGD uptake demonstrated α v β 3 integrin expression in infarcted rat myocardium 1 week after coronary ligation [5].…”

Section: Discussionmentioning

confidence: 99%

Imaging of αvβ3 integrin expression in experimental myocardial ischemia with [68Ga]NODAGA-RGD positron emission tomography

et al. 2017

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BackgroundRadiolabeled RGD peptides detect αvβ3 integrin expression associated with angiogenesis and extracellular matrix remodeling after myocardial infarction. We studied whether cardiac positron emission tomography (PET) with [68Ga]NODAGA-RGD detects increased αvβ3 integrin expression after induction of flow-limiting coronary stenosis in pigs, and whether αvβ3 integrin is expressed in viable ischemic or injured myocardium.MethodsWe studied 8 Finnish landrace pigs 13 ± 4 days after percutaneous implantation of a bottleneck stent in the proximal left anterior descending coronary artery. Antithrombotic therapy was used to prevent stent occlusion. Myocardial uptake of [68Ga]NODAGA-RGD (290 ± 31 MBq) was evaluated by a 62 min dynamic PET scan. The ischemic area was defined as the regional perfusion abnormality during adenosine-induced stress by [15O]water PET. Guided by triphenyltetrazolium chloride staining, tissue samples from viable and injured myocardial areas were obtained for autoradiography and histology.ResultsStent implantation resulted in a partly reversible myocardial perfusion abnormality. Compared with remote myocardium, [68Ga]NODAGA-RGD PET showed increased tracer uptake in the ischemic area (ischemic-to-remote ratio 1.3 ± 0.20, p = 0.0034). Tissue samples from the injured areas, but not from the viable ischemic areas, showed higher [68Ga]NODAGA-RGD uptake than the remote non-ischemic myocardium. Uptake of [68Ga]NODAGA-RGD correlated with immunohistochemical detection of αvβ3 integrin that was expressed in the injured myocardial areas.ConclusionsCardiac [68Ga]NODAGA-RGD PET demonstrates increased myocardial αvβ3 integrin expression after induction of flow-limiting coronary stenosis in pigs. Localization of [68Ga]NODAGA-RGD uptake indicates that it reflects αvβ3 integrin expression associated with repair of recent myocardial injury.

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Association between [68Ga]NODAGA-RGDyK uptake and dynamics of angiogenesis in a human cell-based 3D model

Grönman

Moisio

et al. 2021

Mol Biol Rep

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Radiolabeled RGD peptides targeting expression of αvβ3 integrin have been applied to in vivo imaging of angiogenesis. However, there is a need for more information on the quantitative relationships between RGD peptide uptake and the dynamics of angiogenesis. In this study, we sought to measure the binding of [68Ga]NODAGA-RGDyK to αvβ3 integrin in a human cell-based three-dimensional (3D) in vitro model of angiogenesis, and to compare the level of binding with the amount of angiogenesis. Experiments were conducted using a human cell-based 3D model of angiogenesis consisting of co-culture of human adipose stem cells (hASCs) and of human umbilical vein endothelial cells (HUVECs). Angiogenesis was induced with four concentrations (25%, 50%, 75%, and 100%) of growth factor cocktail resulting in a gradual increase in the density of the tubule network. Cultures were incubated with [68Ga]NODAGA-RGDyK for 90 min at 37 °C, and binding of radioactivity was measured by gamma counting and digital autoradiography. The results revealed that tracer binding increased gradually with neovasculature density. In comparison with vessels induced with a growth factor concentration of 25%, the uptake of [68Ga]NODAGA-RGDyK was higher at concentrations of 75% and 100%, and correlated with the amount of neovasculature, as determined by visual evaluation of histological staining. Uptake of [68Ga]NODAGA-RGDyK closely reflected the amount of angiogenesis in an in vitro 3D model of angiogenesis. These results support further evaluation of RGD-based approaches for targeted imaging of angiogenesis.

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68Ga-NODAGA-RGDyK for αvβ3 integrin PET imaging

Abstract: NODAGA-RGDyK was reliably labeled with 68Ga and revealed a predicted ED of 0.014 mSv/MBq. Tumour uptake was rapid and significant and was chased with unlabeled RGDyK in a similar manner as adrenal uptake.

Cited by 18 publications

References 18 publications

First in-human radiation dosimetry of 68Ga-NODAGA-RGDyK

First in-human radiation dosimetry of 68Ga-NODAGA-RGDyK

Imaging of αvβ3 integrin expression in experimental myocardial ischemia with [68Ga]NODAGA-RGD positron emission tomography

Association between [68Ga]NODAGA-RGDyK uptake and dynamics of angiogenesis in a human cell-based 3D model

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