Radiolabeled (4-Fluoro-3-Iodobenzyl)Guanidine Improves Imaging and Targeted Radionuclide Therapy of Norepinephrine Transporter-Expressing Tumors.

F- or I-labeled (4-fluoro-3-iodobenzyl)guanidine (FIBG) has been a promising yet unattainable derivative of radioiodine-labeled meta-iodobenzylguanidine (MIBG), because of the complex radiofluorination method. In this study, we proposed a 2-step radiosynthetic method to obtain F-FIBG and evaluated the diagnostic and therapeutic potential of F-FIBG and I-FIBG in a pheochromocytoma model (PC-12). F-FIBG was prepared from a (mesityl)(aryl)iodonium salt precursor in the presence of a copper catalyst. Biodistribution studies, PET imaging, and a therapeutic study were performed on the PC-12 xenograft mice with either F- or I-FIBG. The association between the therapeutic effect and the tumor uptake of pretherapy F-FIBG PET was also evaluated. The copper-mediated radiofluorination method readily yielded F-FIBG, as well as its regioisomer, F-IFBG. The isolated F-FIBG showed a higher accumulation in the PC-12 xenograft tumor than in any other tissue. The high tumor uptake of F-FIBG allowed clear tumor visualization in the PET images as early as 1 h after injection, with an excellent tumor-to-background ratio. A biodistribution study with I-FIBG revealed its higher and prolonged retention in the tumor in comparison with I-MIBG. As a result, a therapeutic dose of I-FIBG delayed tumor growth significantly more than did I-MIBG. The tumor uptake of F-FIBG was proportional to the therapeutic effect of I-FIBG. These results suggest the potential usefulness of FIBG as a diagnostic and therapeutic agent for the management of norepinephrine transporter (NET)-expressing tumors.