t-Bu2SiF-derivatized D2-receptor ligands: the first SiFA-containing small molecule radiotracers for target-specific PET-imaging

Molecules. 2011 Sep 2;16(9):7458-79. doi: 10.3390/molecules16097458.

Abstract

The synthesis, radiolabeling and in vitro evaluation of new silicon-fluoride acceptor (SiFA) derivatized D(2)-receptor ligands is reported. The SiFA-technology simplifies the introduction of fluorine-18 into target specific biomolecules for Positron-Emission-Tomography (PET). However, one of the remaining challenges, especially for small molecules such as receptor-ligands, is the bulkiness of the SiFA-moiety. We therefore synthesized four Fallypride SiFA-conjugates derivatized either directly at the benzoic acid ring system (SiFA-DMFP, SiFA-FP, SiFA-DDMFP) or at the butyl-side chain (SiFA-M-FP) and tested their receptor affinities. We found D(2)-receptor affinities for all compounds in the nanomolar range (K(i(SiFA-DMFP)) = 13.6 nM, K(i(SiFA-FP)) = 33.0 nM, K(i(SiFA-DDMFP)) = 62.7 nM and K(i(SiFA-M-FP)) = 4.21 nM). The radiofluorination showed highest yields when 10 nmol of the precursors were reacted with [(18)F]fluoride/TBAHCO(3) in acetonitrile. After a reversed phased cartridge purification the desired products could be isolated as an injectable solution after only 10 min synthesis time with radiochemical yields (RCY) of more than 40% in the case of SiFA-DMFP resulting in specific activities >41 GBq/µmol (>1,100 Ci/mmol). Furthermore, the radiolabeled products were shown to be stable in the injectable solutions, as well as in human plasma, for at least 90 min.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Crystallography, X-Ray
  • Dopamine D2 Receptor Antagonists*
  • Fluorides / chemical synthesis*
  • Fluorides / chemistry
  • Fluorine Radioisotopes / chemistry*
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Positron-Emission Tomography
  • Protein Binding
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Receptors, Dopamine D2 / chemistry
  • Silicon Compounds / chemical synthesis*
  • Silicon Compounds / chemistry

Substances

  • Benzamides
  • Dopamine D2 Receptor Antagonists
  • Fluorine Radioisotopes
  • Radiopharmaceuticals
  • Receptors, Dopamine D2
  • Silicon Compounds
  • silicon fluoride
  • Fluorides