Pilot Study of 18F-BF3-Tyr in Healthy Volunteers and Glioma Patients

Objectives: This work was designed to perform the very-first study of investigating the safety, biodistribution, and radiation dosimetry of large amino acid transporter (LAT) targeting PET tracer 18F-BF3-Tyr in healthy volunteers and to assess receptor expression level in glioma patients.

Methods: A boron-derived tyrosine derivative was synthesized to mimic tyrosine, of which the transportation depends on L-type amino acid transporter type one (LAT-1). 18F-19F isotope exchange reaction was conducted for radiolabelling and quality control was performed by both HPLC and radio TLC. The metabolic stability of 18F-BF3-Tyr was assessed both in vitro and in vivo. PET imaging and bio-distribution studies were performed in mice bearing U87MG xenografts. The animal was scanned at 1-hour post-injection, and followed by sacrificing to do biodistribution at 2-hour post-injection. Two healthy volunteers (1 M, 1 F) underwent whole-body PET acquisitions at multiple time points after bolus injection of 18F-BF3-Tyr (370 ± 148 MBq). Regions of interest (ROIs) were drawn manually over major organs and then the time-activity curves (TACs) were obtained. The dosimetry was calculated using the OLINDA/EXM software. Seven patients with a brain tumor, as diagnosed by contrast-enhanced magnetic resonance imaging (MRI), were enrolled for PET/CT at 30-60 min after 18F-BF3-Tyr injection. After surgical removal, LAT-1 immunohistochemical staining of tumor samples against LAT-1 was performed and correlated with 18F-BF3-Tyr PET.

Results: The radiosynthesis of 18F-BF3-Tyr gives a high radiochemical yield of 30-40% with high radiochemical purity and good reproducibility. The cellular uptake of 18F-BF3-Tyr was found to be highly LAT-1 dependent, and a nearly linear correlation was observed between 18F-BF3-Tyr intake and LAT-1 expression. In an animal with a brain tumor model, 18F-BF3-Tyr exhibits uptake of 6.02±1.58%ID/g in tumor and 0.67±0.01%ID/g in healthy brain tissue. giving a tumor/non-tumor ratio of nearly 10. Injection of 18F-BF3-Tyr was well tolerated in all healthy volunteers, with no serious tracer-related adverse events found. 18F-BF3-Tyr showed rapid clearance from the blood pool and kidneys. The total body absorbed dose and effective dose were 0.00042±0.00049mSv/MBq and 0.00372±0.00516 mSv/MBq, respectively. In 18F-BF3-Tyr PET and 18F-FDG PET brain tumor imaging, the ratio between tumor SUVmax and normal brain tissue SUV was 6.13±2.20 and 0.97±0.32, respectively.

Conclusions: 18F-BF3-Tyr is a PET tracer with favorable pharmacokinetics and dosimetry profile. It has the potential to evaluate LAT-1 expression in glioma patients and provide imaging guidance for further LAT-1 targeted therapy of glioma. A boron-derived Tyr derivative has been developed for imaging LAT-1 expression with PET, suggesting a unique advantage over 18F-FDG on glioma diagnosis.