Synthesis and in vitro examination of [124I]-, [125I]- and [131I]-2-(4-iodophenylamino) pyrido[2,3-d]pyrimidin-7-one radiolabeled Abl kinase inhibitors.

The pyridopyrimidinones are a potent class of inhibitors of c-Abl kinase and Bcr–Abl kinase, the causative fusion protein in chronic myelogenous leukemia and Src family kinases. A novel method for routine, high-yield no-carrier-added synthesis of [ 124 I]-, [ 125 I]- and [ 131 I]-6(2,6-dichlorophenyl)-2-(4-iodophenylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one has been developed. The 4V-trimethylstannyl- or 4Vtri-n-butylstannyl-pyridopyrimidinone precursors were prepared from the aryl bromide via a palladium-mediated coupling with hexaalkylditin (dioxane/microwave irradiation/10 min at 1608C). The radioiodination of 4V-stannylpyridopyrimidinones was found to optimally occur via an iododestannylationwithNa 124 I,Na 125 IorNa 131 Iinthepresenceofanoxidant[30%H2O2/HOAc(1:3)/10min]in79–87%radiochemicalyield with N99% radiochemical purity. The total radiosynthesis time was 30 min. The 4-iodophenylpyridopyrimidinone 2 inhibited recombinant Abl kinase activity with an IC50 of 2.0 nM. Cell proliferation of K562 and A431 cells was inhibited with an IC50 of 2.0 and 20 nM, respectively. Rapid cellular uptake and equilibrium were observed within 10–15 min using [ 131 I]-4-iodophenylpyridopyrimidinone 6c in K562 and A431 cells and demonstrated a 2.8-fold uptake selectivity for the Bcr–Abl-expressing K562 cells at 60 min. These results suggest that pyridopyrimidinone radiotracers may be useful in imaging Abl-, Bcr–Abl- or Src-expressing malignancies.