UCSF

Purpose: Neuroblastoma is an embryonic tumor of the peripheral sympathetic nervous system. Most of neuroblastoma tumors express norepinephrine transporter (NET), which makes metaiodobenzylguanidine (mIBG), an analogue of norepinephrine, an ideal tumor specific agent for therapy, when labeled with I-131. Although drug therapies of neuroblastoma are performed regularly, there is lack of accurate quantitative assessment of tumor response to the therapy. This study was carried out with the objectives: the development of a novel 18F-labeled small molecule-imaging agent that targets the human NET (hNET) receptor, the establishment of a quantitative methodology to assess the therapeutic effect of [131I]mIBG and the establishment of murine xenograft model with a human neuroblastoma cell line that overexpresses hNET for better mIBG uptake would fill an unmet need to further develop treatment for this disease.

Methods: In order to enhance mIBG uptake for therapy, luciferase-expressing and hNET-transduced NB1691 (NB1691-luc-hNET) cells were implanted subcutaneously and in the renal capsule of murine xenograft models. Once the tumors reached a defined volume, the mice were injected with the [18F]RP-109, a NET imaging agent and scanned on the microPET/CT instrument. The xenografts were also imaged using bioluminescence to assess the viability of the cells in vivo. The mice were then treated with [131I]mIBG using an established protocol. Three weeks after the [131I]mIBG treatment, they were re-imaged on the microPET/CT using [18F]RP-109 as well as by bioluminescence. The PET images were then correlated with the bioluminescence scans as well as tumor volume measurements to assess the utility of the probe for monitoring therapy response of the tumors.

Results: The novel probe, [18F]RP-109, was successfully prepared and evaluated in neuroblastoma, but no tumor uptake was observed. The treatment of neuroblastoma with [131I]mIBG therapy showed a better response with higher dose of [131I]mIBG. The therapeutic data obtained from the bioluminescence imaging helps to assess the effectiveness of [131I]mIBG treatment of neuroblastoma model and evaluate the functional status of tumors.

Conclusion: The NET probe was successfully radiolabelled with fluorine-18 and it did not show any visible uptake in the tumors that overexpress hNET. The [131I]MIBG therapy study in mouse models using bioluminescence and tumor volume measurement as follow-up showed the effective therapy at 2 mCi level, which was consistent with the estimated tumor dosimetry study performed previously.