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

Objectives: 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 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.

Methods: [18F]FBY was radiolabeled through 18F 19F isotope exchange reaction. Computational studies and competitive inhibitory assay were conducted to study the mechanism of cellular uptake of FBY. Stability of FBY was monitored by HPLC. In vivo small animal [18F]FBY PET imaging and biodistribution studies were conducted. The correlation between PET images and boron concentrations of tumor and major organs was studied under the condition of injection with the mixture of trace amount of [18F]FBY along with a therapeutic dose of FBY. At last, the effectiveness of FBY BNCT was evaluated on mice bearing B16F10 tumors.

Results: [18F]FBY was synthesized in high radiochemical yield (50%) and high radiochemical purity (98%). FBY showed high similarity with natural tyrosine. The uptake of FBY in B16F10 cells was LAT1 dependent and reached up to 128 ppm. FBY displayed high stability. [18F]FBY PET showed high accumulation in the tumor and notably low normal tissue uptake (Tumor to Muscle = 3.16 ± 0.48; Tumor to Blood = 3.13 ± 0.50; Tumor to Brain = 14.25 ± 1.54). Moreover, administration of [18F]FBY tracer along with a therapeutic dose of FBY showed high accumulation in the tumor and low normal tissue uptake. Correlation between PET image and boron biodistribution was established, indicating the possibility to estimate boron concentration via a non invasive approach. At last, with thermal irradiation, mice injected with FBY showed significantly elongated median survival without exhibiting obvious systemic toxicity.

Conclusions: FBY BNCT provides excellent control over the growth of B16F10 melanoma cancer. Moreover, FBY holds great potential for being an efficient theranostic agent for imaging guided BNCT for the brain tumor, the lung and the liver metastases by offering a possible solution of measuring local boron concentration via PET imaging.

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