A Metabolically Stable Boron-Derived Tyrosine Serves as a Theranostic Agent for Positron Emission Tomography Guided Boron Neutron Capture Therapy.

Abstract

Boronophenylalanine (BPA) is the dominant boron delivery agent for boron neutron capture therapy (BNCT), and [18F]FBPA has been developed to assist the treatment planning for BPA-BNCT. However, the clinical application of BNCT has been limited by its inadequate tumor specificity due to the metabolic instability. In addition, the distinctive molecular structures between [18F]FBPA and BPA can be of concern as [18F]FBPA cannot quantitate boron concentration of BPA in a real-time manner. In this study, a metabolically stable boron-derived tyrosine (denoted as fluoroboronotyrosine, FBY) was developed as a theranostic agent for both boron delivery and cancer diagnosis, leading to PET imaging-guided BNCT of cancer. [18F]FBY was synthesized in high radiochemical yield (50%) and high radiochemical purity (98%). FBY showed high similarity with natural tyrosine. As shown in in vitro assays, the uptake of FBY in murine melanoma B16-F10 cells was L-type amino acid transporter (LAT-1) dependent and reached up to 128 μg/106 cells. FBY displayed high stability in PBS solution. [18F]FBY PET showed up to 6 %ID/g in B16-F10 tumor and notably low normal tissue uptake (tumor/muscle = 3.16 ± 0.48; tumor/blood = 3.13 ± 0.50; tumor/brain = 14.25 ± 1.54). Moreover, administration of [18F]FBY tracer along with a therapeutic dose of FBY showed high accumulation in B16-F10 tumor and low normal tissue uptake. Correlation between PET-image and boron biodistribution was established, indicating the possibility of estimating boron concentration via a noninvasive approach. At last, with thermal neutron irradiation, B16-F10 tumor-bearing mice injected with FBY showed significantly prolonged median survival without exhibiting obvious systemic toxicity. In conclusion, FBY holds great potential as an efficient theranostic agent for imaging-guided BNCT by offering a possible solution of measuring local boron concentration through PET imaging.

• Authors: Jiyuan Li, Yaxin Shi, Zizhu Zhang, Hui Liu, Lixin Lang, Tong Liu, Xiaoyuan Chen, Zhibo Liu
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 30 Issue 11 Pg. 2870-2878 (11 20 2019) ISSN: 1520-4812 [Electronic] United States
• PMID: 31593447 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fluorine Radioisotopes
• Radiopharmaceuticals
• Tyrosine
• Boron

Topics

• Animals
• Boron (chemistry)
• Boron Neutron Capture Therapy (methods)
• Cell Cycle
• Cell Proliferation
• Female
• Fluorine Radioisotopes (pharmacokinetics)
• Melanoma, Experimental (diagnostic imaging, metabolism, radiotherapy)
• Mice
• Mice, Inbred C57BL
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (pharmacokinetics)
• Theranostic Nanomedicine
• Tissue Distribution
• Tumor Cells, Cultured
• Tyrosine (analogs & derivatives, pharmacokinetics)