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

Silvano Gnesin, Periklis Mitsakis, Francesco Cicone, Emmanuel Deshayes, Vincent Dunet, Augusto F Gallino, Marek Kosinski, Sébastien Baechler, Franz Buchegger, David Viertl, John O Prior, Silvano Gnesin, Periklis Mitsakis, Francesco Cicone, Emmanuel Deshayes, Vincent Dunet, Augusto F Gallino, Marek Kosinski, Sébastien Baechler, Franz Buchegger, David Viertl, John O Prior

Abstract

Background: Integrin-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.

Results: The 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.

Conclusions: According 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 registration: Clinical trial.gov, NCT01608516.

Keywords: 68Ga-NODAGA-RGDyK; Angiogenesis; Choroid plexuses; Dosimetry; Integrin αvβ3; PET/CT.

Figures

Fig. 1
Fig. 1
From left to right, example of maximum intensity projections 10, 60 and 120 min post tracer injection showing 68Ga-NODAGA-RGDyK uptake distribution in major abdominal organs. In this patient case, retention of radio-urine in the excretory system is exacerbated by prostatic hypertrophy
Fig. 2
Fig. 2
Typical uptake pattern in the choroid plexuses of the lateral ventricles. Left-hand site panel shows 68Ga-NODAGA-RGDyK absence of uptake in the frontal horns of the lateral ventricles. The central and right-hand side panels show increased uptake in the occipital and temporal horns of the lateral ventricles, while only faint uptake is seen in the plexus of the third ventricle
Fig. 3
Fig. 3
68Ga-NODAGA-RGDyK time-activity concentrations for some of the most irradiated organs. The organ activity was normalized to the injected activity and organ mass (%IA/g). Blue circles at each time point indicates the measurements for the five patients enrolled in this study. Solid lines represent the mono-exponential fits and error bars indicate ±SD. The coefficient of determination (R2) of the fit is reported for each organ
Fig. 4
Fig. 4
Organ time-activity curves corrected for 68Ga physical decay. These data essentially show the biological organ kinetics of 68Ga-NODAGA-RGDyK during the observation time. Colour bars represent the average percent of injected activity per gram of tissue (%IA/g) ± standard deviation

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