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 (18)F-fluorodeoxyglucose ((18)F-FDG) with that of (68)Ga-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 (68)Ga-NODAGA-RGD and of (18)F-FDG were compared with PET imaging in the same animals, along with additional autohistoradiographic analyses and blocking tests for (68)Ga-NODAGA-RGD. RESULTS: Both tracers showed a primary renal route of clearance, although with faster clearance for (68)Ga-NODAGA-RGD resulting in higher activities in the kidneys and bladder. The tumor activity from (68)Ga-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 (68)Ga-NODAGA-RGD decreased progressively with time, contrary to that of (18)F-FDG, although (68)Ga-NODAGA-RGD exhibited 3.4 and 3.7-fold higher tumor-to-normal brain ratios on average compared to (18)F-FDG in mice and rat models, respectively. Finally, ex-vivo analyses revealed that the tumor areas with high (68)Ga-NODAGA-RGD uptake also exhibited the highest rates of cell proliferation and αv integrin expression, irrespective of cell density. CONCLUSIONS: (68)Ga-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.