PET imaging of 68 Ga-NODAGA-RGD, as compared with 18 F-fluorodeoxyglucose, in experimental rodent models of engrafted glioblastoma

Abstract

Background

Tracers 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.

Methods

Nude 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.

Results

Both 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 2^nd 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.

Conclusions

⁶⁸Ga-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 2^nd hour following injection in order to provide sufficiently high integrin specificity.

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