Abstract
BackgroundTracers triggering αvβ3 integrins, such as certain RGD-containing peptides, were found promising in previous pilot studies characterizing high-grade gliomas. However, only limited comparisons have been performed with current PET tracers. This study aimed at comparing the biodistribution of 18F-fluorodeoxyglucose (18F-FDG) with that of 68Ga-NODAGA-RGD, an easily synthesized monomeric RGD compound with rapid kinetics, in two different rodent models of engrafted human glioblastoma.MethodsNude rodents bearing human U87-MG glioblastoma tumor xenografts in the flank (34 tumors in mice) or in the brain (5 tumors in rats) were analyzed. Kinetics of 68Ga-NODAGA-RGD and of 18F-FDG were compared with PET imaging in the same animals, along with additional autohistoradiographic analyses and blocking tests for 68Ga-NODAGA-RGD.ResultsBoth tracers showed a primary renal route of clearance, although with faster clearance for 68Ga-NODAGA-RGD resulting in higher activities in the kidneys and bladder. The tumor activity from 68Ga-NODAGA-RGD, likely corresponding to true integrin binding (i.e., suppressed by co-injection of a saturating excess of unlabeled RGD), was found relatively high, but only at the 2nd hour following injection, corresponding on average to 53% of total tumor activity. Tumor uptake of 68Ga-NODAGA-RGD decreased progressively with time, contrary to that of 18F-FDG, although 68Ga-NODAGA-RGD exhibited 3.4 and 3.7-fold higher tumor-to-normal brain ratios on average compared to 18F-FDG in mice and rat models, respectively. Finally, ex-vivo analyses revealed that the tumor areas with high 68Ga-NODAGA-RGD uptake also exhibited the highest rates of cell proliferation and αv integrin expression, irrespective of cell density.Conclusions68Ga-NODAGA-RGD has a high potential for PET imaging of glioblastomas, especially for areas with high integrin expression and cell proliferation, although PET recording needs to be delayed until the 2nd hour following injection in order to provide sufficiently high integrin specificity.
Highlights
Tracers triggering αvβ3 integrins, such as certain RGD-containing peptides, were found promising in previous pilot studies characterizing high-grade gliomas
The diagnostic information obtained with 18F-fluorodeoxyglucose (18F-FDG) is somewhat variable whereas amino acid positron emission tomography (PET) tracers, such as 11C-methionine, 18F-FDOPA, and 18F-FET, allow a more accurate, tumor characterization [3], which may be the case for more recent radiotracers developed for PET imaging of αvβ3 integrins [4, 5]
The overall process, including synthesizer test, cassette test, radiosynthesis, and quality control leading to the production of around 250 MBq of 68Ga-NODAGA-RGD, lasted approximately 60 min
Summary
Tracers triggering αvβ integrins, such as certain RGD-containing peptides, were found promising in previous pilot studies characterizing high-grade gliomas. The diagnostic information obtained with 18F-fluorodeoxyglucose (18F-FDG) is somewhat variable whereas amino acid PET tracers, such as 11C-methionine, 18F-FDOPA, and 18F-FET, allow a more accurate, tumor characterization [3], which may be the case for more recent radiotracers developed for PET imaging of αvβ integrins [4, 5]. These integrins are currently expressed in glioma cells and in neo-vessel endothelial cells, in conjunction with tumor-related angiogenic processes [6]. While some of these RGD-containing peptides have been labeled with Fluor-18, their synthesis appears to be too complex for routine applications despite their high diagnostic potential [9, 12]
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