Synthesis of (99m)Tc-EC-AMT as an imaging probe for amino acid transporter systems in breast cancer.

Abstract

OBJECTIVE:

This study was to develop a (99m)Tc-labeled alpha-methyl tyrosine (AMT) using L,L-ethylenedicysteine (EC) as a chelator and to evaluate its potential in breast tumor imaging in rodents.

METHODS:

EC-AMT was synthesized by reacting EC and 3-bromopropyl AMT (N-BOC, ethyl ester) in ethanol/potassium carbonate solution. EC-AMT was labeled with (99m)Tc in the presence of tin (II) chloride. Rhenium-EC-AMT (Re-EC-AMT) was synthesized as a reference standard for (99m)Tc-EC-AMT. To assess the cellular uptake kinetics of (99m)Tc-EC-AMT, 13 762 rat breast cancer cells were incubated with (99m)Tc-EC-AMT for 0-2 h. To investigate the transport mechanism, the same cell line was used to conduct the competitive inhibition study using L-tyrosine. Tissue distribution of (99m)Tc-EC-AMT was determined in normal rats at 0.5-4 h. Planar imaging of breast tumor-bearing rats was performed at 30 and 90 min. The data were compared with those of (18)F-2-fluoro-2-deoxy-glucose. Blocking uptake study using unlabeled AMT was conducted to investigate the transport mechanism of (99m)Tc-EC-AMT in vivo.

RESULTS:

Structures of EC-AMT and Re-EC-AMT were confirmed by nuclear magnetic resonance, high performance liquid chromatography and mass spectra. In-vitro cellular uptake of (99m)Tc-EC-AMT in 13,762 cells was increased as compared with that of (99m)Tc-EC and could be inhibited by L-tyrosine. Biodistribution in normal rats showed high in-vivo stability of (99m)Tc-EC-AMT. Planar scintigraphy at 30 and 90 min showed that (99m)Tc-EC-AMT could clearly visualize tumors. (99m)Tc-EC-AMT uptake could be significantly blocked by unlabeled AMT in vivo.

CONCLUSION:

The results indicate that (99m)Tc-EC-AMT, a new amino acid transporter-based radiotracer, is suitable for breast tumor imaging.

• Authors: Fan-Lin Kong, YinHan Zhang, Mohammad S Ali, Chanksok Oh, Richard Mendez, Saady Kohanim, Ning Tsao, Mithu Chanda, Wen-Chien Huang, David J Yang
• Journal: Nuclear medicine communications (Nucl Med Commun) Vol. 31 Issue 8 Pg. 699-707 (Aug 2010) ISSN: 1473-5628 [Electronic] England
• PMID: 20495499 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Transport Systems
• Chelating Agents
• Organotechnetium Compounds
• ethylene dicysteine
• alpha-Methyltyrosine
• Cysteine

Topics

• Amino Acid Transport Systems (metabolism)
• Animals
• Biological Transport (drug effects)
• Breast Neoplasms (diagnostic imaging, metabolism, pathology)
• Cell Line, Tumor
• Chelating Agents (chemistry)
• Cysteine (analogs & derivatives, chemistry)
• Female
• Molecular Imaging (methods)
• Organotechnetium Compounds (chemical synthesis, chemistry, metabolism, pharmacokinetics)
• Positron-Emission Tomography
• Rats
• alpha-Methyltyrosine (chemistry, pharmacology)