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Gallium-68 is rapidly gaining importance, as this generator-produced PET isotope is available independent of on-site cyclotrons, enabling radiopharmaceutical production with comparably simple techniques at low cost. The recently introduced TRAP chelator combines the advantage of straightforward design of multimeric ⁶⁸Ga-radiopharmaceuticals with very fast and efficient ⁶⁸Ga-labeling. We synthesized a series of five cyclo(RGDfK) peptide trimers and determined their α(v)β₃ integrin affinities in competition assays on α(v)β₃-expressing M21 human melanoma cells against ¹²⁵I-echistatin. The compound with highest IC₅₀, Ga-TRAP(RGD)₃, showed more than 7-fold higher affinity compared to the monomers F-Galacto-RGD and Ga-NODAGA-c(RGDyK). TRAP(RGD)₃ was radiolabeled with ⁶⁸Ga in a fully automated GMP compliant manner. CD-1 athymic nude mice bearing M21/M21L human melanoma xenografts were used for biodistribution studies, blockade experiments, metabolite studies and PET imaging. ⁶⁸Ga-TRAP(RGD)₃ exhibited high M21 tumor uptake (6.08±0.63% ID/g, 60 min p.i.), was found to be fully stable in vivo, and showed a fast renal clearance. Blockade studies showed that uptake in the tumor, as well as in all other tissues, is highly integrin specific. A comparison of biodistribution and PET data of ⁶⁸Ga-TRAP(RGD)₃ with those of ⁶⁸Ga-NODAGA-c(RGDyK) and ¹⁸F-Galacto-RGD showed that the higher affinity of the trimer effects a larger dynamic response of tracer uptake to integrin expression, i.e., enhanced integrin-specific uptake in all tissues. We conclude that ⁶⁸Ga-TRAP(RGD)₃ could allow for imaging of low-level integrin expression in tissues which are not visible with the two competitors. Overall, the study constitutes proof of concept for the favourable in vivo properties of TRAP-based ⁶⁸Ga radiopharmaceuticals., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: (18)F-Galacto-cyclo(RGDfK) is a well investigated tracer for imaging of ανβ3 expression in vivo, but suffers from the drawback of a time consuming multistep synthesis that can hardly be established under GMP conditions. In this study, we present a direct comparison of the pharmacokinetic properties of this tracer with (68)Ga-NODAGA-cyclo(RGDyK), in order to assess its potential as an alternative for (18)F-Galacto-cyclo(RGDfK)., Methods: (68)Ga labeling of NODAGA-cyclo(RGDyK) was done in full automation using HEPES-buffered eluate of an SnO(2) based (68)Ga-generator. Using M21 (human melanoma) xenografted BALB/c nude mice, biodistribution studies and micro-PET scans were performed for both (18)F-Galacto-cyclo(RGDfK) and (68)Ga-NODAGA-cyclo(RGDyK), and for the latter, in vivo stability was assessed. IC(50) was determined in a displacement assay on M21 cells against (125)I-echistatin., Results: (68)Ga-NODAGA-cyclo(RGDyK) was produced with high specific activity (routinely ca. 500 GBq/μmol) within 15 min. IC(50) values are similar for both substances. Tracer uptake was similar in ανβ3 positive tumors (1.45%±0.11% ID/g and 1.35%±0.53% ID/g for (68)Ga-NODAGA-RGD and (18)F-Galacto-RGD, respectively) as well as for all other organs and tissues, with the exception of gall bladder and intestines, where (18)F-Galacto-cyclo(RGDfK) uptake was significantly higher, which can be explained by the higher hydrophilicity of (68)Ga-NODAGA-cyclo(RGDyK) (logP=-4.0 vs. -3.2 for (18)F-Galacto-RGD). Only intact tracer was detected 30 min p.i. in organs and tumor; however, minor amounts of metabolites were found in the urine (6% of total urine activity)., Conclusion: (68)Ga-labeling of NODAGA-RGD can be performed rapidly and efficiently within 15 min in a GMP compliant process. Similar preclinical results were obtained in comparison with (18)F-Galacto-RGD. Therefore, (68)Ga-NODAGA-cyclo(RGDyK) is a suitable replacement for (18)F-Galacto-cyclo(RGDfK)., (Copyright © 2012 Elsevier Inc. All rights reserved.)