Synthesis of 18F-labelled 2-(4'-fluorophenyl)-1,3-benzothiazole and evaluation as amyloid imaging agent in comparison with [11C]PIB

Bioorg Med Chem Lett. 2009 Feb 1;19(3):602-5. doi: 10.1016/j.bmcl.2008.12.069. Epub 2008 Dec 24.

Abstract

2-(4'-[(18)F]fluorophenyl)-1,3-benzothiazole was synthesized as a fluorine-18 labelled derivative of the Pittsburg Compound-B (PIB), which has known affinity for amyloid beta and promising characteristics as tracer for in vivo visualisation of amyloid deposits in patients suffering from Alzheimer's disease (AD). Both the nitro-precursor 2-(4'-nitrophenyl)-1,3-benzothiazole and the non-radioactive reference compound were synthesized using a 1-step synthesis pathway. Labelling was achieved by direct aromatic nucleophilic substitution of the nitro-precursor using [(18)F]fluoride by heating for 20 min at 150 degrees C and with a radiochemical yield of 38%. The reference compound showed high affinity for amyloid in an in vitro competition binding study using human AD brain homogenates (K(i)=9.0 nM) and fluorescence imaging of incubated transgenic APP mouse brain slices confirmed binding to amyloid plaques. A biodistribution study in normal mice showed a high brain uptake at 2 min pi (3.20%ID/g) followed by a fast washout (60 min pi: 0.21%ID/g). A dynamic microPET study was performed in a transgenic APP and normal WT mouse, but, similar to [(11)C]PIB, no difference was seen in tracer retention between both kind of mice. The new (18)F-labelled 2-phenylbenzothiazole showed excellent preclinical characteristics comparable with those of the (11)C-labelled PIB.

MeSH terms

  • Alzheimer Disease / drug therapy
  • Amyloid / chemistry
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Benzothiazoles / chemical synthesis
  • Benzothiazoles / chemistry*
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Fluorine Radioisotopes / chemistry*
  • Humans
  • Kinetics
  • Mice
  • Mice, Transgenic
  • Models, Chemical
  • Temperature
  • Tissue Distribution

Substances

  • 2-(4'-fluorophenyl)-1,3-benzothiazole
  • Amyloid
  • Amyloid beta-Protein Precursor
  • Benzothiazoles
  • Fluorine Radioisotopes
  • benzothiazole