Evaluation of radioiodinated quinazoline derivative as a new ligand for EGF receptor tyrosine kinase activity using SPECT.
OBJECTIVE
A radioiodinated analog of PD153035 (m-IPQ) was evaluated as a potential epidermal growth factor receptor tyrosine kinase (EGFR-TK) activity imaging ligand for SPECT.


METHODS
The 50% inhibition concentration (IC₅₀) value of m-IPQ for EGFR-TK phosphorylation inhibition was evaluated and compared to various EGFR-TK inhibitors. [(125)I]m-IPQ was synthesized by iododestannylation reaction. Biodistribution study of [(125)I]m-IPQ was conducted in normal mice and tumor-bearing mice. The selectivity and binding characteristics (B(max) and K(d)) were analyzed.


RESULTS
The quinazoline derivative m-IPQ was found to have high inhibitory potency (IC₅₀: 50.5 ± 3.5 nM) and selectivity toward EGFR-TK. In vivo biodistribution studies of [(125)I]m-IPQ demonstrated its rapid clearance and low retention in normal tissue. On the other hand, high tumor uptake was observed. However, the increase in [(125)I]m-IPQ uptake in the stomach as a deiodination parameter was found. Thus, [(125)I]m-IPQ showed low in vivo stability. The selectivity toward EGFR-TK of m-IPQ was confirmed by the pretreatment experiment with EGFR-TK specific inhibitors, PD153035, Genistein. [(125)I]m-IPQ bound to single population of binding sites with high affinity and kinetic parameter. In addition, [(125)I]m-IPQ was bound to EGFR-TK according to the amount of EGFR-TK expression in the tumor.


CONCLUSIONS
[(125)I]m-IPQ showed a relatively high tumor accumulation with selective EGFR-TK binding. Moreover, the tumor uptake of [(125)I]m-IPQ might be reflected in the amount of EGFR-TK expression in the tumor. These good characteristics of [(125)I]m-IPQ suggested that a ¹²³I-labeled counterpart, [¹²³I]m-IPQ, would have great potential for EGFR-TK imaging with SPECT. However, the in vivo stability of this compound needs to improve.
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan.
Masahiko
M
Hirata
Yasukazu
Y
Kanai
Sadahiro
S
Naka
Keiji
K
Matsumuro
Shinya
S
Kagawa
Mitsuyoshi
M
Yoshimoto
Yoshiro
Y
Ohmomo
D000818:Animals; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry; D008024:Ligands; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D013379:Substrate Specificity; D015899:Tomography, Emission-Computed, Single-Photon
D007457:Iodine Radioisotopes; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline