Evaluation of the novel TSPO radiotracer 2-(7-butyl-2-(4-(2-([18F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide in a preclinical model of neuroinflammation

Eur J Med Chem. 2018 Apr 25:150:1-8. doi: 10.1016/j.ejmech.2018.02.076. Epub 2018 Feb 24.

Abstract

Translocator Protein (18 kDa, TSPO) is regarded as a useful biomarker for neuroinflammation imaging. TSPO PET imaging could be used to understand the role of neuroinflammation in brain diseases and as a tool for evaluating novel therapeutic effects. As a promising TSPO probe, [18F]DPA-714 is highly specific and offers reliable quantification of TSPO in vivo. In this study, we further radiosynthesized and evaluated another novel TSPO probe, 2-(7-butyl-2-(4-(2-[18F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([18F]VUIIS1018A), which features a 700-fold higher binding affinity for TSPO than that of [18F]DPA-714. We evaluated the performance of [18F]VUIIS1018A using dynamic in vivo PET imaging, radiometabolite analysis, in vitro autoradiography assays, biodistribution analysis, and blocking assays. In vivo study using this probe demonstrated high signal-to-noise ratio, binding potential (BPND), and binding specificity in preclinical neuroinflammation studies. Taken together, these findings indicate that [18F]VUIIS1018A may serve as a novel TSPO PET probe for neuroinflammation imaging.

Keywords: Neuroinflammation; Positron Emission Tomography (PET); TSPO; [(18)F]DPA-714; [(18)F]VUIIS1018A.

MeSH terms

  • Animals
  • Disease Models, Animal*
  • Dose-Response Relationship, Drug
  • Fluorine Radioisotopes
  • Humans
  • Inflammation / diagnosis*
  • Inflammation / metabolism
  • Ischemia / diagnosis*
  • Ischemia / metabolism
  • Male
  • Mice
  • Molecular Probes / chemistry*
  • Molecular Structure
  • Positron-Emission Tomography
  • Pyrazoles
  • Pyrimidines
  • Radioactive Tracers
  • Radiopharmaceuticals / chemistry*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA / analysis*
  • Structure-Activity Relationship
  • Tissue Distribution

Substances

  • 2-(7-butyl-2-(4-(2-(((18)F)fluoroethoxy)phenyl)-5-methylpyrazolo(1,5-a)pyrimidin-3-yl)-N,N-diethylacetamide
  • Fluorine Radioisotopes
  • Molecular Probes
  • Pyrazoles
  • Pyrimidines
  • Radioactive Tracers
  • Radiopharmaceuticals
  • Receptors, GABA
  • TSPO protein, human