18F-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 68Ga-NODAGA-cyclo(RGDyK), in order to assess its potential as an alternative for 18F-Galacto-cyclo(RGDfK).

Methods

68Ga labeling of NODAGA-cyclo(RGDyK) was done in full automation using HEPES-buffered eluate of an SnO2 based 68Ga-generator. Using M21 (human melanoma) xenografted BALB/c nude mice, biodistribution studies and micro-PET scans were performed for both 18F-Galacto-cyclo(RGDfK) and 68Ga-NODAGA-cyclo(RGDyK), and for the latter, in vivo stability was assessed. IC50 was determined in a displacement assay on M21 cells against 125I-echistatin.

Results

68Ga-NODAGA-cyclo(RGDyK) was produced with high specific activity (routinely ca. 500 GBq/μmol) within 15 min. IC50 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 68Ga-NODAGA-RGD and 18F-Galacto-RGD, respectively) as well as for all other organs and tissues, with the exception of gall bladder and intestines, where 18F-Galacto-cyclo(RGDfK) uptake was significantly higher, which can be explained by the higher hydrophilicity of 68Ga-NODAGA-cyclo(RGDyK) (logP = −4.0 vs. − 3.2 for 18F-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

68Ga-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 18F-Galacto-RGD. Therefore, 68Ga-NODAGA-cyclo(RGDyK) is a suitable replacement for 18F-Galacto-cyclo(RGDfK).

Pancreatic ductal adenocarcinoma (PDAC) and its precursor lesions, pancreatic intraepithelial neoplasia (PanIN), display a ductal phenotype. However, there is evidence in genetically defined mouse models for PDAC harbouring a mutated kras under the control of a pancreas-specific promoter that ductal cancer might arise in the centroacinar-acinar region, possibly through a process of acinar-ductal metaplasia (ADM). In order to further elucidate this model of PDAC development, an extensive expression analysis and molecular characterization of the putative and already established (PanIN) precursor lesions were performed in the Kras$^{G{\it{\bf{12}}}D/+}$ ; Ptf1a-Cre$^{ex{\it{\bf{1}}}/+}$ mouse model and in human tissues, focusing on lineage markers, developmental pathways, cell cycle regulators, apomucins, and stromal activation markers. The results of this study show that areas of ADM are very frequent in the murine and human pancreas and represent regions of increased proliferation of cells with precursor potential. Moreover, atypical flat lesions originating in areas of ADM are the most probable precursors of PDAC in the Kras$^{G{\it{\bf{12}}}D/+}$; Ptf1a-Cre$^{ex{\it{\bf{1}}}/+}$ mice and similar lesions were also found in the pancreas of three patients with a strong family history of PDAC. In conclusion, PDAC development in Kras$^{G{\it{\bf{12}}}D/+}$; Ptf1a-Cre$^{ex{\it{\bf{1}}}/+}$ mice starts from ADM and a similar process might also take place in patients with a strong family history of PDAC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.