¹⁸F-Trifluoroborate Derivatives of [Des-Arg¹⁰]Kallidin for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography

Abstract

Bradykinin B1 receptor (B1R) is involved in pain and inflammation pathways and is upregulated in inflamed tissues and cancer. Due to its minimal expression in healthy tissues, B1R is an attractive target for the development of therapeutic agents to treat inflammation, chronic pain, and cancer. The goal of this study is to synthesize and compare two (18)F-labeled peptides derived from potent B1R antagonists B9858 and B9958 for imaging B1R expression with positron emission tomography (PET). Azidoacetyl-B9858 2 and azidoacetyl-B9958 3 were synthesized by a solid-phase approach and subsequently clicked to ammoniomethyl-trifluoroborate (AmBF3)-conjugated alkyne 1 to obtain AmBF3-B9858 and AmBF3-B9958, respectively. AmBF3-B9858 and AmBF3-B9958 bound B1R with high affinity, with Ki values at 0.09 ± 0.08 and 0.46 ± 0.03 nM, respectively, as measured by in vitro competition binding assays. (18)F labeling was performed via an (18)F-(19)F isotope exchange reaction. The radiofluorinated tracers were obtained within a synthesis time of 30 min and with 23-32% non-decay-corrected radiochemical yield, >99% radiochemical purity, and 43-87 GBq/μmol specific activity at the end of the synthesis. PET imaging and biodistribution studies were carried out in mice bearing both B1R-positive (B1R(+)) HEK293T::hB1R and B1R-negative (B1R(-)) HEK293T tumors. Both tracers cleared rapidly from most organs/tissues, mainly through the renal pathway. High uptake in B1R(+) tumors ((18)F-AmBF3-B9858: 3.94 ± 1.24% ID/g, tumor-to-muscle ratio 21.3 ± 4.33; (18)F-AmBF3-B9958: 4.20 ± 0.98% ID/g, tumor-to-muscle ratio 48.6 ± 10.7) was observed at 1 h postinjection. These results indicate that (18)F-AmBF3-B9858 and (18)F-AmBF3-B9958 are promising agents for the in vivo imaging of B1R expression with PET.

Radiolabeled B9958 Derivatives for Imaging Bradykinin B1 Receptor Expression with Positron Emission Tomography: Effect of the Radiolabel–Chelator Complex on Biodistribution and Tumor Uptake

“…[6][7][8] However, the only reported B1R-trageting tracer composed of B9958 and Pip was 18 F-L08060 (Fig. 1).…”

“…In addition, direct 18 F-19 F isotope exchange reaction on AmBF 3 -conjugated molecules has been shown to generate 18 Flabeled analogs with good radiochemical yield (~ 10 -20%) and specific activity (~ 74 GBq/µmol), and has been successfully applied for the design and preparation of a variety of PET tracers. 8,[11][12][13][14][15] Despite excellent binding affinity (K i = 0.5 nM), the uptake in B1R+ tumor and tumor-tobackground contrast ratios of 18 F-L08060 were inferior to those of 68 Ga-P04158 and 68 Ga-Z02090 (Table 1). 68 Ga-P04158 and 68 Ga-Z02090 were derived from different targeting sequences (B9858 and B9958, respectively), but shared the same radiolabel-chelator complex ( 68 Ga-DOTA) and linker (dPEG2).…”

“…Both strategies could be performed directly in aqueous solution, and have been successfully applied for the design of 18 Flabeled peptide-based PET tracers. 8,[14][15][16][17][18][19][20] For 68 Ga-labeling, we compared the use of NODA and a well-established chelator DOTA.…”

Design, synthesis and evaluation of18F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging

“…Stability in plasma was performed following published procedures 47,48 . Aliquots (100 lL) of 18 F-labeled 2 were incubated with 400 lL of balb/c mouse plasma (Innovative Research, Novi, MI) for upwards of 60 min at 37 C. At the end of each incubation period, samples were quenched by addition of acetonitrile (0.5 mL), centrifuged to remove proteins, and finally passed through a 0.2 micron filter.…”

Synthesis of meta-substituted [18F]3-fluoro-4-aminopyridine via direct radiofluorination of pyridine N-oxides

“…As far as we know, this represents the first example of fluoride exchange of a C-F bond in a heterocyclic compound. Producing tracers by fluoride exchange limits the final specific activity as the radioactive product cannot be separated from the cold one, however, there are recent examples in which tracers produced by fluoride exchange achieved excellent specific radioactivities ranging from 1–3 Ci/µmol (37–111 GBq/µmol) 16, 17 . Finally, we tested fluorination of the corresponding pyridines not containing a nitro group and found that 3-bromopyridine N-oxide can also undergo halogen exchange suggesting a broad scope for this reaction.…”