Transport mechanism and affinity of [99mTc]Tc-mercaptoacetyltriglycine ([99mTc]MAG3) on the apical membrane of renal proximal tubule cells

Masato Kobayashi; Kodai Nishi; Asuka Mizutani; Hiroyuki Okudaira; Takeo Nakanishi; Naoto Shikano; Ryuichi Nishii; Ikumi Tamai; Keiichi Kawai

doi:10.1016/j.nucmedbio.2020.01.002

Transport mechanism and affinity of [99mTc]Tc-mercaptoacetyltriglycine ([99mTc]MAG3) on the apical membrane of renal proximal tubule cells

Nucl Med Biol. 2020 May-Jun:84-85:33-37. doi: 10.1016/j.nucmedbio.2020.01.002. Epub 2020 Jan 15.

Authors

Masato Kobayashi¹, Kodai Nishi², Asuka Mizutani³, Hiroyuki Okudaira⁴, Takeo Nakanishi⁵, Naoto Shikano⁶, Ryuichi Nishii⁷, Ikumi Tamai⁸, Keiichi Kawai⁹

Affiliations

¹ School of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan. Electronic address: kobayasi@mhs.mp.kanazawa-u.ac.jp.
² Department of Radioisotope Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
³ School of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan.
⁴ Research and Business Development Department, Nihon Medi-Physics Co., Ltd., Tokyo, Japan.
⁵ Faculty of Pharmacy, Takasaki University of Health and Welfare, Gunma, Japan.
⁶ Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, Ibaraki, Japan.
⁷ Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, Chiba, Japan.
⁸ School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan.
⁹ School of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan; Biomedical Imaging Research Center, University of Fukui, Fukui, Japan.

PMID: 31986465
DOI: 10.1016/j.nucmedbio.2020.01.002

Abstract

Technetium-99m-labeled mercaptoacetyltriglycine ([^99mTc]MAG3) is widely used for evaluation of transplanted kidneys, diagnosis of tubular necrosis, and scintigraphic studies of tubular function. [^99mTc]MAG3 is a substrate for organic anion transporter (OAT)1 and OAT3 on the basolateral membrane side for renal secretion. We investigated the transport mechanism and affinity of [^99mTc]MAG3 on the apical membrane of renal proximal tubule cells for renal secretion. Adenosine triphosphate-binding cassette (ABC) transporters for renal secretion of [^99mTc]MAG3 were examined using ABC transporter vesicles expressing multiple drug resistance 1 (MDR1), breast cancer resistance protein (BCRP), multidrug resistance-associated protein (MRP)2, and MRP4. MK-571, a MRP inhibitor, was applied to measure the K_m and V_max of MRP2 and MRP4 in a vesicle transport assay. Single photon emission computed tomography (SPECT) was performed in normal rats and MRP2-deficient Eisai hyperbilirubinuria rats (EHBR) using [^99mTc]MAG3 with and without MK-571. [^99mTc]MAG3 uptake in adenosine triphosphate was significantly higher than that in adenosine monophosphate in vesicles that highly expressed MRP2 and MRP4. The affinity of [^99mTc]MAG3 for MRP4 was higher than that for MRP2. Renal secretion via MRP2 and MRP4 was identified by comparing normal and EHBR rats with and without MK-571 on SPECT. [^99mTc]MAG3 is transported via MRP2 and MRP4 on the apical membrane of renal proximal tubule cells. The affinity of MRP4 is higher than that of MRP2. SIGNIFICANCE STATEMENT: [^99mTc]MAG3, widely used for evaluation of transplanted kidneys, diagnosis of tubular necrosis, and scintigraphic studies of tubular function, is transported via MRP2 and MRP4 on the apical membrane of renal proximal tubule cells. The affinity of MRP4 is higher than that of MRP2.

Keywords: Adenosine triphosphate-binding cassette transporters; Renal proximal tubule cells; Renal scintigraphy; Single photon emission computed tomography imaging; [(99m)Tc]MAG3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biological Transport
Cell Membrane / metabolism*
Kidney Tubules, Proximal / cytology*
Kidney Tubules, Proximal / diagnostic imaging
Rats
Technetium Tc 99m Mertiatide / metabolism*
Tomography, Emission-Computed, Single-Photon

Substances

Technetium Tc 99m Mertiatide