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An Artificial Amino Acid, 4-Iodo-L-meta-Tyrosine: Biodistribution and Excretion via Kidney

¹ Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, Ibaraki, Japan
² School of Health Sciences, Faculty of Medicine, Kanazawa University, Ishikawa, Japan
³ Department of Radiology, Miyazaki Medical College, Miyazaki, Japan
⁴ Faculty of Pharmaceutical Sciences, Science University of Tokyo, Tokyo, Japan

We evaluated the use of radiolabeled 4-iodo-L-meta-tyrosine as an amino acid transport marker. The pharmacologic features of this compound, particularly the biodistribution and excretion, were examined by conducting in vivo and in vitro studies using 4-¹²⁵I-iodo-L-meta-tyrosine (4-¹²⁵I-mTyr). Results obtained for L-¹⁴C-Tyr and 3-¹²⁵I-iodo--methyl-L-tyrosine (¹²⁵I-IMT) were used for comparison. Methods: In vivo biodistribution studies of 4-¹²⁵I-mTyr were performed in male ddY mice. Urinary excretion of 4-¹²⁵I-mTyr and ¹²⁵I-IMT with administration of probenecid was studied. Local distribution of 4-¹²⁵I-mTyr and ¹²⁵I-IMT in kidney was visualized by autoradiography. We performed metabolite analysis of 4-¹²⁵I-mTyr in mice. For in vitro studies, reabsorption mechanisms of 4-¹²⁵I-mTyr were compared with those of ¹²⁵I-IMT and the parent L-¹⁴C-Tyr using superconfluent monolayers of the porcine kidney epithelial cell line LLC-PK₁ in medium containing inhibitor (L-Tyr, D-Tyr, and 2,4-dinitrophenol), in Na⁺-free medium, and at 4°C. Results: 4-¹²⁵I-mTyr demonstrated high accumulation in the pancreas and kidney and comparable brain uptake to that of ¹²⁵I-IMT. Blood clearance of 4-¹²⁵I-mTyr was faster than that of ¹²⁵I-IMT. Three hours after administration, >70% of 4-¹²⁵I-mTyr was excreted via the urine, whereas <5% was found in the feces. Renal autoradiography revealed moderate accumulation of 4-¹²⁵I-mTyr and high accumulation of ¹²⁵I-IMT in the renal cortex. Probenecid further reduced accumulation of 4-¹²⁵I-mTyr and ¹²⁵I-IMT in the kidney as well as urinary excretion. At 30 min after tracer injection, intact free 4-¹²⁵I-mTyr accounted for >98.1% of the total present in kidney and >96.3% in urine. Protein incorporation was not observed. Uptake of 4-¹²⁵I-mTyr into LLC-PK₁ cell monolayers was remarkably reduced by 5 mmol/L L-Tyr (4.6%) and incubation at 4°C (15.6%) but was reduced by 5 mmol/L D-Tyr (50.0%). L-¹⁴C-Tyr and ¹²⁵I-IMT showed similar results; however, uptake of ¹²⁵I-IMT was enhanced by 0.1 mmol/L 2,4-dinitrophenol (165.1%), an inhibitor of generation of energy-rich phosphates. Conclusion: The artificial amino acid 4-¹²⁵I-mTyr demonstrated high metabolic stability, rapid blood clearance, rapid urinary excretion, and similar biodistribution to other radiolabeled L-Tyr analogs. 4-¹²⁵I-mTyr can be a competitive substrate of L-Tyr reabsorption. However, 4-¹²⁵I-mTyr demonstrates different pharmacologic features than those of ¹²⁵I-IMT, particularly in renal handling. 4-¹²⁵I-mTyr may potentially be applied as a new amino acid transport marker.

Key Words: amino acid transport • artificial amino acid • LLC-PK₁ • 4-iodo-L-meta-tyrosine • SPECT