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 4'-trimethylstannyl- or 4'-tri-n-butylstannyl-pyridopyrimidinone precursors were prepared from the aryl bromide via a palladium-mediated coupling with hexaalkylditin (dioxane/microwave irradiation/10 min at 160 degrees C). The radioiodination of 4'-stannylpyridopyrimidinones was found to optimally occur via an iododestannylation with Na(124)I, Na(125)I or Na(131)I in the presence of an oxidant [30% H(2)O(2)/HOAc (1:3)/10 min] in 79-87% radiochemical yield with >99% radiochemical purity. The total radiosynthesis time was 30 min. The 4-iodophenylpyridopyrimidinone 2 inhibited recombinant Abl kinase activity with an IC(50) of 2.0 nM. Cell proliferation of K562 and A431 cells was inhibited with an IC(50) 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.
Veach
Darren R
DR
Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Namavari
Mohammad
M
Beresten
Tatiana
T
Balatoni
Julius
J
Minchenko
Maria
M
Djaballah
Hakim
H
Finn
Ronald D
RD
Clarkson
Bayard
B
Gelovani
Juri G
JG
Bornmann
William G
WG
Larson
Steven M
SM
D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D007457:Iodine Radioisotopes / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000000981:diagnostic imaging / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000009:adverse effects / Q000138:chemical synthesis / Q000493:pharmacokinetics
C546822:2-(4-iodophenylamino)pyrido(2,3-d)pyrimidin-7-one; D007457:Iodine Radioisotopes; C115711:PD 173074; D011728:Pyridones; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl