Radiolabeled meta-iodobenzylguanidine (mIBG) is an important radiopharmaceutical used in the diagnosis and treatment of neuroendocrine cancers. mIBG is known to enter tumor cells through the norepinephrine transporter. Whole-body scintigraphy has shown rapid mIBG elimination through the kidney and high accumulation in several normal tissues, but the underlying molecular mechanisms are unclear. Using transporter-expressing cell lines, we show that mIBG is an excellent substrate for human organic cation transporters 1-3 (hOCT1-3) and the multidrug and toxin extrusion proteins 1 and 2-K (hMATE1/2-K), but not for the renal organic anion transporter 1 and 3 (hOAT1/3). Kinetic analysis revealed that hOCT1, hOCT2, hOCT3, hMATE1, and hMATE2-K transport mIBG with similar apparent affinities (K

Transporters on the plasma membrane of tumor cells are promising molecular "Trojan horses" to deliver drugs and imaging agents into cancer cells. Radioiodine-labeled metaiodobenzylguanidine (mIBG) is used as a diagnostic agent ( 123 I-mIBG) and a targeted radiotherapy ( 131 I-mIBG) for neuroendocrine cancers. mIBG enters cancer cells through the norepinephrine transporter (NET) where the radioactive decay of 131 I causes DNA damage, cell death, and tumor necrosis. mIBG is predominantly eliminated unchanged by the kidney.Despite its selective uptake by neuroendocrine tumors, mIBG accumulates in several normal tissues and leads to tissue-specific radiation toxicities. Emerging evidences suggest that the polyspecific organic cation transporters play important roles in systemic disposition and tissuespecific uptake of mIBG. In particular, human organic cation transporter 2 (hOCT2) and toxin extrusion proteins 1 and 2-K (hMATE1/2-K) likely mediate renal secretion of mIBG whereas hOCT1 and hOCT3 may contribute to mIBG uptake into normal tissues such as the liver, salivary glands, and heart. This mini-review focuses on the clinical applications of mIBG in neuroendocrine cancers and the differential roles of NET, OCT and MATE transporters in mIBG disposition, response and toxicity. Understanding the molecular mechanisms governing mIBG transport in cancer and normal cells is a critical step for developing strategies to optimize the efficacy of 131 I-mIBG while minimizing toxicity in normal tissues.

This toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary. The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects information for these toxic substances described therein. Each peer-reviewed profile identifies and reviews the key literature that describes a substance's toxicologic properties. Other pertinent literature is also presented, but is described in less detail than the key studies. The profile is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced. CAS# 7439-92-1

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