Synthesis, fluorine-18 radiolabeling, and biological evaluation of N-((E)-4-fluorobut-2-en-1-yl)-2beta-carbomethoxy-3beta-(4'-halophenyl)nortropanes: candidate radioligands for in vivo imaging of the brain dopamine transporter with positron emission tomography

J Med Chem. 2010 Aug 12;53(15):5549-57. doi: 10.1021/jm100269c.

Abstract

The N-(E)-fluorobutenyl-3beta-(para-halo-phenyl)nortropanes 9-12 were synthesized as ligands of the dopamine transporter (DAT) for use as (18)F-labeled positron emission tomography (PET) imaging agents. In vitro competition binding assays demonstrated that compounds 9-12 have a high affinity for the DAT and are selective for the DAT compared to the serotonin and norepinephrine transporters. MicroPET imaging with [(18)F]9-[(18)F]11 in anesthetized cynomolgus monkeys showed high uptake in the putamen with lesser uptake in the caudate, but significant washout of the radiotracer was only observed for [(18)F]9. PET imaging with [(18)F]9 in an awake rhesus monkey showed high and nearly equal uptake in both the putamen and caudate with peak uptake achieved after 20 min followed by a leveling-off for about 10 min and then a steady washout and attainment of a quasi-equilibrium. During the time period 40-80 min postinjection of [(18)F]9, the ratio of uptake in the putamen and caudate vs cerebellum uptake was > or = 4.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding, Competitive
  • Brain / metabolism*
  • Caudate Nucleus / metabolism
  • Cerebellum / metabolism
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Fluorine Radioisotopes
  • Humans
  • Ligands
  • Macaca fascicularis
  • Nortropanes / chemical synthesis*
  • Nortropanes / chemistry
  • Nortropanes / pharmacokinetics
  • Positron-Emission Tomography
  • Putamen / metabolism
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Fluorine Radioisotopes
  • Ligands
  • N-(4-fluorobut-2-en-1-yl)-2-carbomethoxy-3-(4'-fluorophenyl)nortropane
  • Nortropanes
  • Radiopharmaceuticals