Presentation Abstract

Abstract Number: 836
Presentation Title: In vivo PET imaging of MET receptor in human cancer using [11C]SU11274
Presentation Time: Sunday, Apr 18, 2010, 2:00 PM - 5:00 PM
Location: Exhibit Hall A-C, Poster Section 31
Poster Section: 31
Poster Board Number: 25
Author Block: Patrick C. Ma1, Chunying Wu2, Zhe Tang1, Weiwen Fan1, Wenxia Zhu2, Changning Wang2, Edurado Somoza2, Norbert Owino2, Ruoshi Li2, Yanming Wang2. 1Division of Hematology/Oncology, Case Western Reserve University School of Medicine, Cleveland, OH; 2Division of Radiopharmaceutical Science, Case Center for Imaging Research, Department of Radiology, Case Western Reserve University, Cleveland, OH
Abstract Body: The mesenchymal-epithelial transition (MET) receptor plays prominent role in human tumorigenesis, tumor progression and metastasis. Overexpression or mutation of MET results in activation of oncogenic signaling pathways and leads to upregulation of diverse tumor cell functions. Mounting evidence has validated MET receptor as novel target for anticancer therapy. For efficacy evaluation of various MET-targeted anticancer therapies currently under development, it is critical to develop an imaging tool that permits detection and quantification of MET expression in vivo. To date, a number of small molecule MET inhibitors have been developed, including SU11274, which is a specific, reversible MET inhibitor that induces apoptosis in cells transformed by activated MET kinase. Here, we report the radiosynthesis and evaluation of a molecular imaging probe, [11C]SU11274, for quantification of MET receptors in human cancers in vivo. The radiolabeling with C-11 was accomplished through radiomethylation using 3-[3,5-Dimethyl-4-(piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-2-oxo-2,3-dihyro-1H-indole-5-sulfonic acid (3-chlorophenyl)-methyl amide hydrochloride as a key precursor. Following the synthesis of the precursor that was achieved in 10 steps with a total yield of 9.7%, [11C]SU11274 was obtained through radiomethylation in a range of 5-10 % radiochemical yield and over 95% radiochemical purity. For in vivo PET studies, two human lung adenocarcinoma cancer xenograft models were established using MET-positive H1975 and MET-negative H520 cell lines. The time-radioactivity curves showed that the uptake of [11C]SU11274 in the H1975 xenograft was significantly higher than in the H520 xenograft (p = 0.00019). Compared to H520, the H1975 xenograft mice exhibited an increased tumor uptake of [11C]SU11274 throughout the entire measurement period of 90 min. At 65 min post-injection, the radioactivity concentration ratio of H1975/H520 reached a statistically significant and enhanced ratio of 2.1, and peaked at 2.6 at 80 min. The PET imaging results were consistent with their corresponding immunohistochemical tissue staining patterns of MET receptors from the same animals. Hence, our results suggest that [11C]SU11274-PET is a specific imaging marker that can differentiate and quantify MET receptor expression in vivo. These studies demonstrated that [11C]SU11274-PET can facilitate the clinical development of MET-targeted cancer therapeutics.