68Ga-NODAGA-RGDyK for αvβ3 integrin PET imaging Preclinical investigation and dosimetry

Aim: To visualize neovasculature and/or tumour integrin alpha(v)beta(3), we selected the binding moiety Arg-Gly-Asp-D-Tyr-Lys (RGDyK) coupled to NODAGA for labeling with Ga-68. Methods: NODAGA-RGDyK (ABX) was labeled with the Ga-68 eluate from the Ge-68 generator IGG100 using the processor unit PharmTracer. Biodistribution was measured in female Hsd mice sacrificed 10, 30, 60 and 90 min after i.v. injection of Ga-68-NODAGA-RGDyK for OLINDA dosimetry extrapolated to humans. Tumour targeting was studied in SCID mice bearing A431 and other tumour transplants using microPET and biodistribution measurements. Results: Effective half-life of Ga-68-NODAGA-RGDyK was similar to 25 min for total body and most organs except liver and spleen that showed stable activity retention.with a bladder voiding interval of 0.5 h the calculated effective dose (ED) was 0.012 and 0.016 mSv/MBq for males and females, respectively. Rapid uptake within 10 min was observed in A431 tumours with dynamic PET followed by a slow release. Biodistribution measurements showed a Ga-68-NODAGA-RGDyK uptake in A431 tumours of 3.4 +/- 0.4 and 2.7 +/- 0.3%ID/g at 1 and 2 h, respectively. Similar uptakes were observed in a mouse and human breast and ovarian cancer xenografts. Co-injection of excess (5 mg/kg) unlabeled NODAGA-RGDyK with the radiotracer reduced tumour uptake at one hour to 0.23 +/- 0.01%ID/g, but similarly decreased uptake in normal organs as well.When unlabeled peptide was injected 15 min after Ga-68-NODAGA-RGDyK, uptake diminished particularly in tumour and adrenals, suggestive of a different binding mode compared with other normal tissues. Conclusion: NODAGA-RGDyK was reliably labeled with Ga-68 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.