Abstract 2678: First demonstration of in vivo PET imaging for ALK inhibitor using [11C]ASP3026, a novel brain-permeable type of ALK inhibitor.
Authors: Fushiki Hiroshi , Saito Rika , Jitsuoka Makoto , Shimada Itsuro , Kondoh Yutaka , Sakagami Hideki , Funatsu Yukiko , Noda Akihiro , Murakami Yoshihiro , Miyoshi Sousuke , Ueno Yoko , Konagai Satoshi , Soga Takatoshi , Nishimura Shintaro , Mori Masamichi , Kuromitsu Sadao 
Published: August 2014

Abstract
The recent breakthrough identifying the onco-driver fusion mutant of ALK kinase and its inhibitor crizotinib commercially termed as Xalkori has brought significant benefit to a portion of non-small cell lung cancer (NSCLC) patients. However, a number of clinical issues in ALK-positive lung cancer remain, involving resistance to crizotinib caused by secondary mutation, amplification of the ALK gene, activation of alternative pathways, and metastatic resistance, etc. Among these mechanisms, brain metastasis is a critical issue because of its poor prognosis. We have recently identified ASP3026 as a novel type of ALK inhibitor under development, and have reported that ASP3026 shows antitumor activities in several crizotinib-refractory models including gate keeper mutants. Here, we report the first PET imaging of an ALK inhibitor using [11C]ASP3026. The study has revealed that ASP3026 shows a brain tumor permeability in an intracranial xenograft model of H2228-luc ALK fusion positive cells. In this model, significant growth inhibition of H2228 intracranial tumor was observed by treatment with ASP3026 (10 mg/kg, q.d.), but not with crizotinib (10 mg/kg, q.d.) as determined by a bioluminescent imaging technique. Pharmacokinetic measurements of ASP3026 and crizotinib indicated that ASP3026 showed a four-fold better brain penetration than crizotinib on AUC0-24 base analysis, with a brain/plasma ratio=0.72 and 0.18 for ASP3026 and crizotinib, respectively. Further, we synthesized positron-labeled [11C]ASP3026 and performed PET imaging to clarify penetration of ASP3026 into cranial tumors. Quantitative analysis of [11C]ASP3026-PET data indicated that ASP3026 showed higher uptake into cranial tumors (SUV=3.0) than brain parenchyma (SUV=0.8). Moreover, comparison of pharmacokinetic profiles in several tumor models showed that tumor uptake of ASP3026 was higher than that of surrounding tissue, suggesting that tumor accumulation of ASP3026 was dependent on the microenvironment of tumor. Taken together, these results suggest that ASP3026 has favorable properties that may be useful for the treatment of brain metastases in ALK-positive NSCLC patients. Thus, PET imaging using 11C-labeled ASP3026 may allow the tumor penetration of ASP3026 to be clarified in any primary or metastatic tumor site.
Citation Format: Hiroshi Fushiki, Rika Saito, Makoto Jitsuoka, Itsuro Shimada, Yutaka Kondoh, Hideki Sakagami, Yukiko Funatsu, Akihiro Noda, Yoshihiro Murakami, Sousuke Miyoshi, Yoko Ueno, Satoshi Konagai, Takatoshi Soga, Shintaro Nishimura, Masamichi Mori, Sadao Kuromitsu. First demonstration of in vivo PET imaging for ALK inhibitor using [11C]ASP3026, a novel brain-permeable type of ALK inhibitor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2678. doi:10.1158/1538-7445.AM2013-2678