Synthesis and evaluation of a radioiodinated lumiracoxib derivative for the imaging of cyclooxygenase-2 expression
| Autor: | Nagara Tamaki, Koh ichi Seki, Yumiko Katada, Naoyuki Obokata, Hideo Saji, Yuji Kuge, Hiroyuki Kimura, Kazuki Aita, Yukihiko Sugimoto, Takashi Temma |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Cancer Research Pathology medicine.medical_specialty Biodistribution Diclofenac Metabolic Clearance Rate Pharmacology Cell Line Iodine Radioisotopes Rats Sprague-Dawley In vivo medicine Animals Tissue Distribution Radiology Nuclear Medicine and imaging Radionuclide Imaging Cyclooxygenase 2 Inhibitors medicine.diagnostic_test biology Chemistry Macrophages biochemical phenomena metabolism and nutrition Rats Cyclooxygenase 2 Organ Specificity Positron emission tomography Cell culture Isotope Labeling biology.protein bacteria Molecular Medicine Lumiracoxib Cyclooxygenase Preclinical imaging Ex vivo medicine.drug |
| Zdroj: | Nuclear Medicine and Biology. 36:869-876 |
| ISSN: | 0969-8051 |
| Popis: | Introduction Despite extensive attempts to develop cyclooxygenase (COX)-2 imaging radiotracers, no suitable positron emission tomography (PET)/single photon emission computed tomography (SPECT) tracers are currently available for in vivo imaging of COX-2 expression. The aims of this study were to synthesize and evaluate a radioiodinated derivative of lumiracoxib, 2-[(2-fluoro-6-iodophenyl)-amino]-5-methylphenylacetic acid (FIMA), which is structurally distinct from other drugs in the class and has weakly acidic properties, as a SPECT tracer for imaging COX-2 expression. Methods The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation with hydrogen peroxide. Cell uptake characteristics of 125 I-FIMA were assessed in control and linterfero/interferon-γ-stimulated macrophages. The biodistribution of 125 I-FIMA was determined by the ex vivo tissue counting method in rats. Results The COX-2 inhibitory potency of FIMA (IC 50 =2.46 μM) was higher than that of indomethacin (IC 50 =20.9 μM) and was comparable to lumiracoxib (IC 50 =0.77 μM) and diclofenac (IC 50 =0.98 μM). The IC 50 ratio (COX-1/COX-2=182) indicated FIMA has a high isoform selectivity for COX-2. 125 I-FIMA showed a significantly higher accumulation in COX-2 induced macrophages than in control macrophages, which decreased with nonradioactive FIMA in a concentration dependent manner. The biodistribution study showed rapid clearance of 125 I-FIMA from the blood and most organs including the liver and kidneys. No significant in vivo deiodination was observed with radioiodinated FIMA. Conclusions FIMA showed high inhibitory potency and selectivity for COX-2. Radioiodinated FIMA showed specific accumulation into COX-2 induced macrophages, no significant in vivo deiodination and rapid blood clearance. Radioiodinated FIMA deserves further investigation as a SPECT radiopharmaceutical for imaging COX-2 expression. |
| Databáze: | OpenAIRE |
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