Interaction of the Plasma Membrane Monoamine Transporter and Organic Cation Transporters with Meta‐iodobenzylguanidine (mIBG)

Abstract

Meta‐iodobenzylguanidine (mIBG) is a radiopharmaceutical used as both a diagnostic imaging agent (123I‐mIBG) and a targeted frontline radiotherapy (131I‐mIBG) for neuroblastoma. Scintigraphic imaging of mIBG in human and biodistribution studies in xenografted animal models have shown that alongside its uptake into neuroblastoma tumor tissues, mIBG is also significantly transported into normal organs and tissues including the liver, salivary glands, and kidney. 123I‐or 131I‐mIBG accumulation in normal tissues can interfere with its tumor imaging quality and contribute to peripheral toxicities. While mIBG uptake into the neuroblastoma tumors has been shown to be facilitated predominantly by the human norepinephrine transporter (hNET), the molecular mechanisms involved in its uptake into the peripheral tissues have been poorly understood. We hypothesized that the organic cation transporters 1–3 (hOCT1‐3) and the human plasma membrane monoamine transporter (hPMAT) are involved in mIBG transport and accumulation in normal tissues. Thus, the purpose of this project is to characterize the interaction and transport kinetics of mIBG with these transporters and compare them with hNET. This was done by executing uptake assays in human embryonic kidney cells stably expressing hPMAT, hNET, or hOCT1‐3, followed with mIBG quantification by liquid chromatography‐tandem mass spectrometry. Time‐dependent studies showed that mIBG is an excellent substrate of hPMAT, hNET, and hOCT1‐3. Concentration‐dependent studies were fitted to the Michaelis‐Menten equation, resulting in Km values for hPMAT, hNET, and hOCT2 of 42.0 ± 10.7, 35.7 ± 8.91, and 42.9 ± 12.5 μM, respectively, suggesting that mIBG has a similar apparent affinity towards these transporters. Our data demonstrated that mIBG is a novel substrate for hPMAT and hOCTs, providing a molecular basis for these transporters as potential facilitators for mIBG uptake into normal tissues.Support or Funding InformationThis work is supported by NIH Grants GM066233 and T32‐GM007750.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.