¹⁸F-BF₃-B9858: A promising PET tracer for imaging bradykinin B1 receptor expression in cancer

Objectives Bradykinin B1 receptor (B1R), overexpressed in a variety of malignancies but not in normal tissues, is a promising biomarker for cancer imaging. Herein, we report the synthesis and evaluation of an ¹⁸F-labeled peptide derived from the potent antagonist B9858 (Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic) for imaging B1R expression with PET.

Methods Azidoacetyl-4-amino-(1-carboxymethyl)piperidine-B9858 was synthesized and subsequently clicked to an alkyne-BF₃ to obtain BF₃-B9858. Binding affinity (Ki) of BF₃-B9858 was measured via competition binding assays using B1R expressing CHO-K1 cell membranes. ¹⁸F-labeling was performed via ¹⁸F-¹⁹F isotope exchange reaction followed by SPE purification using a C18 Sep-Pak cartridge. PET imaging and biodistribution studies were performed in NODSCID gamma mice (n=4) bearing both B1R- HEK293T and B1R+ HEK293T:hB1R tumors.

Results BF₃-B9858 bound B1R with high affinity (Ki = 0.083 ± 0.074 nM). ¹⁸F-BF₃-B9858 was prepared in 30 min synthesis time, and isolated in ~25% (n=3) radiochemical yield with >99% radiochemical purity and >100 GBq/µmol specific activity. ¹⁸F-BF₃-B9858 was stable in plasma with <1% decomposition after 2 h incubation at room temperature. PET imaging and biodistribution showed that radioactivity was cleared rapidly from most organs/tissues, and excreted mainly through the renal pathway. High uptake in B1R+ tumor (7.46±3.97 %ID/g) was observed at 1h post-injection, and the bone uptake (0.51±0.20 %ID/g) was minimal. Uptake ratios of B1R+ tumor to liver, blood, muscle and B1R- tumor at 1h post-injection were 10.8±4.6, 11.7±3.4, 41.4±22.7 and 14.8±3.5, respectively.

Conclusions ¹⁸F-BF₃-B9858 was prepared efficiently in a short synthesis time via ¹⁸F-¹⁹F isotope exchange, and generated high contrast images of B1R+ tumors in mice. These results suggest ¹⁸F-BF₃-B9858 is a promising B1R PET tracer, which warrants further evaluation.