Design, synthesis and evaluation of (18)F-labeled bradykinin B1 receptor-targeting small molecules for PET imaging

Bioorg Med Chem Lett. 2016 Aug 15;26(16):4095-100. doi: 10.1016/j.bmcl.2016.06.066. Epub 2016 Jun 27.

Abstract

Two fluorine-18 ((18)F) labeled bradykinin B1 receptor (B1R)-targeting small molecules, (18)F-Z02035 and (18)F-Z02165, were synthesized and evaluated for imaging with positron emission tomography (PET). Z02035 and Z02165 were derived from potent antagonists, and showed high binding affinity (0.93±0.44 and 2.80±0.50nM, respectively) to B1R. (18)F-Z02035 and (18)F-Z02165 were prepared by coupling 2-[(18)F]fluoroethyl tosylate with their respective precursors, and were obtained in 10±5 (n=4) and 22±14% (n=3), respectively, decay-corrected radiochemical yield with >99% radiochemical purity. (18)F-Z02035 and (18)F-Z02165 exhibited moderate lipophilicity (LogD7.4=1.10 and 0.59, respectively), and were stable in mouse plasma. PET imaging and biodistribution studies in mice showed that both tracers enabled visualization of the B1R-positive HEK293T::hB1R tumor xenografts with better contrast than control B1R-negative HEK293T tumors. Our data indicate that small molecule antagonists can be used as pharmacophores for the design of B1R-targeting PET tracers.

Keywords: Antagonist; Bradykinin B1 receptor; Fluorine-18; Molecular imaging; Positron emission tomography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bradykinin B1 Receptor Antagonists / chemical synthesis
  • Bradykinin B1 Receptor Antagonists / chemistry
  • Bradykinin B1 Receptor Antagonists / metabolism*
  • Drug Design*
  • Fluorine Radioisotopes / chemistry
  • HEK293 Cells
  • Humans
  • Methylamines / chemical synthesis
  • Methylamines / chemistry
  • Methylamines / metabolism*
  • Mice
  • Neoplasms / diagnostic imaging
  • Positron-Emission Tomography*
  • Protein Binding
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / metabolism
  • Receptor, Bradykinin B1 / chemistry
  • Receptor, Bradykinin B1 / metabolism*
  • Tissue Distribution
  • Transplantation, Heterologous

Substances

  • 2-(2-(((4-methoxy-2,6-dimethylphenyl)sulfonyl)methylamino)ethoxy)acetyl chloride
  • Bradykinin B1 Receptor Antagonists
  • Fluorine Radioisotopes
  • Methylamines
  • Radiopharmaceuticals
  • Receptor, Bradykinin B1

Grants and funding