The development of meta-iodobenzylguanidine analogues for the therapy of neuroendocrine and other tumours

Radioiodinated meta-iodobenzylguanidine (MIBG) has been extensively used in the diagnosis and therapy of neuroendocrine tumours such as neuroblastoma. We have developed a no-carrier-added synthesis (n.c.a.) for MIBG as well as other analogues which may improve clinical utility. In SK-N-SH human neuroblastoma cells in vitro, the uptake of n.c.a. [131I]MIBG remained constant over a 2-3-log activity concentration range. In contrast, the uptake of [131 I]MIBG prepared by an exchange radioiodination (ex-[131I]MIBG) steadily decreased over the same range demonstrating the saturability of uptake under these conditions. Similar differences in uptake were seen in normal mouse heart and adrenals, the normal target tissues for MIBG. While no advantage of n.c.a [131 I]MIBG over ex-[131I]MIBG was seen in athymic mice hosting SK-N-SH neuroblastoma xenografts, higher tumour uptake and tumour-to-normal tissue ratios were observed when SK-N- BE(2C) xenografts were used. Since neuroblastoma is often associated with micrometastases, an MIBG analogue labelled with the -particle emitting 211At could be advantageous. A method has been developed for the efficient synthesis of meta-[211At]astatobenzylguanidine (MABG). A number of in vitro assays and tissue distribution studies showed that MABG is an excellent analogue of MIBG. From clonogenic assays using SK-N-SH neuroblastoma cells, it was calculated that the D0 value for MABG (215 Bq/ml) was more than 1000-fold lower than that of n.c.a. [131I]MIBG. A 18F-labelled analogue of MIBG, 4-[18 F]fluoro-3-iodobenzylguanidine ([18 F]FIBG), has been prepared and is shown to have a higher uptake in SK-N-SH cells than MIBG. Because it may be an invaluable tool in combination with [18 F]FIBG, a method has been developed for the synthesis of its radioiodinated analogue, [131I]FIBG. It was shown that SK-N-SH cells retained FIBG to a significantly higher degree than MIBG over a 3-day period, suggesting that [131I]FIBG may deliver a higher integrated dose to the tumour than [131I]MIBG. (author)