The New Molecular Probe - ¹⁸ F-BF ₃ -Phe In The Basic Imaging Of Tumor Imaging And Clinical Transformation

ObjectiveThis 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-Phe in healthy volunteers and to assess receptor expression level in glioma patients.MethodsA boron-derived pheylalanine derivative was synthesized to mimic Phe, 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-Phe was assessed both in vitro and in vivo. PET imaging and bio-distribution studies were performed in mice bearing PC9、BXPC3、PC3、HEPG2 xenografts. 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-Phe (370±148 MBq). Regions of interest (ROls) were drawn manually over major organs and then the time-activity curves (TACs) were obtained. Dosimetry was calculated using the OLINDA/EXM software. Seven patients with brain tumor, as diagnosed by contrast-enhanced magnetic resonance imaging (MRI), were enrolled for PET/CT at 30-60 min after 18F-BF3-Phe injection. After surgical removal, LAT-1 immunohistochemical staining of tumor samples against LAT-1 was performed and correlated with 18F-BF3-Phe PET.ResultsThe radiosynthesis of 18F-BF3-Phe gives high radiochemical yield of 30-40% with high radiochemical purity and good reproducibility. The cellular uptake of 18F-BF3-Phe was found to be highly LAT-1 dependent, and a nearly linear correlation was observed between 18F-BF3-Phe intake and LAT-1 expression. As expected, PET images showed that 18F-BF3-Phe has intense accumulation in PC9、BXPC3、PC3、HEPG2 tumor and low uptake in the rest of the body. The tracer had predominant renal clearance but with low kidney retention. In animal with lung cancer model,18F-BF3-Phe exhibits uptake of 4.16±2.00% ID/g in tumor and 1.39±0.18%ID/g in healthy lung tissue,giving tumor/non-tumor ratio of more than 3. In animal with pancreatic cancer model, 18F-BF3-Phe exhibits uptake of 10.29±0.73%ID/g in tumor and 2.71±0.66%ID/g in healthy pancrease tissue, giving tumor/non-tumor ratio of 3.8. In animal with brain tumor model,18F-BF3-Phe exhibits uptake of 6.02±1.58%ID/g in tumor and 0.67±0.01%ID/g in healthy brain tissue, giving tumor/non-tumor ratio of nearly 10. Injection of 18F-BF3-Phe was well tolerated in all healthy volunteers, with no serious tracer-related adverse events found.18F-BF3-Phe 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-Phe PET and 18F-FDG PET brain tumor imaging, the ratio between tumor SUVmax and normal brain tissue SUV were 6.13±2.20 and 0.97±0.32, respectively.Conclusion18F-BF3-Phe 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 Phe derivative has been developed for imaging LAT-1 expression with PET, suggesting a unique advantage over 18F-FDG on glioma diagnosis.