Synthesis of carbon-11-labeled 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine derivatives as new potential PET tracers for imaging of p38α mitogen-activated protein kinase

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3700-5. doi: 10.1016/j.bmcl.2014.07.017. Epub 2014 Jul 12.

Abstract

The reference standards methyl 4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (10a), methyl 4-(2-methyl-5-(ethoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (10b) and corresponding precursors 4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (11a), methyl 4-(2-methyl-5-(ethoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (11b) were synthesized from methyl crotonate and 3-amino-4-methylbenzoic acid in multiple steps with moderate to excellent yields. The target tracer [(11)C]methyl 4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate ([(11)C]10a) and [(11)C]methyl 4-(2-methyl-5-(ethoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate ([(11)C]10b) were prepared from their corresponding precursors with [(11)C]CH3OTf under basic condition through O-[(11)C]methylation and isolated by a simplified solid-phase extraction (SPE) method in 50-60% radiochemical yields at end of bombardment (EOB) with 185-555 GBq/μmol specific activity at end of synthesis (EOS).

Keywords: Cancer; Carbon-11-labeled 4-(phenylamino)-pyrrolo[2,1-f][1,2,4]triazine derivatives; Diabetes; Inflammation; Positron emission tomography (PET); p38α mitogen-activated protein kinase (MAPK).

Publication types

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

MeSH terms

  • Carbon Radioisotopes
  • Diagnostic Imaging*
  • Dose-Response Relationship, Drug
  • Humans
  • Mitogen-Activated Protein Kinase 14 / analysis*
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Molecular Structure
  • Positron-Emission Tomography*
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Radiopharmaceuticals* / chemistry
  • Radiopharmaceuticals* / pharmacology
  • Structure-Activity Relationship
  • Triazines / chemistry
  • Triazines / pharmacology*

Substances

  • Carbon Radioisotopes
  • Protein Kinase Inhibitors
  • Pyrroles
  • Radiopharmaceuticals
  • Triazines
  • Mitogen-Activated Protein Kinase 14