Abstract 5227: Detection of metastatic potential by a novel small molecule F-18 PET imaging agent
Authors: Zhu Aizhi , Yoon Younghyoun , Liang Zhongxing , Voll Ronald , Goodman Matthew E. , Goodman Mark M. , Shim Hyunsuk 
Published: June 2012

Squamous cell carcinoma (SCC), a malignant tumor of epithelial origin, represents more than 90% of all head and neck cancers. While lymph node metastases are more common in SCCHN patients (∼60%), approximately 20 to 25% of patients with SCCHN develop distant metastases, primarily in the lungs, liver, and bone. We established metastatic SCCHN subclones from a poorly metastatic parental cell line by in vivo selection. These metastatic subclones expressed high levels of CXCR4 chemokine receptor while non-metastatic parental cells did not, which suggests that CXCR4 is required for metastatic progression. CXCR4 plays a key role as a homing receptor to the lymph nodes, lung, liver, and bone. Homing, the mechanism that allows foreign tissue-origin cells to reside and proliferate, is believed to be the rate-limiting step of the multi-step metastatic process. Therefore, CXCR4 overexpression can be a predictor of the metastatic potential and the lethality of tumor cells. Here, we developed a novel small molecule CXCR4-reporting PET tracer. We have identified a novel small molecule CXCR4 antagonist, N, N′-(1,4-phenylenebis(methylene)) dipyrimidin-2-amines (M508F), through rational design by analysis of emerging structural and functional data. Its binding potency (EC50) is &lt;10 nM in a binding affinity assay, with a great inhibitory efficacy against CXCR4/CXCL12-mediated Matrigel invasion and cAMP reduction. [18F]M508F was generated from M508Cl by a one-step chloride substitution. This reaction yield was reproducibly 30%. Biodistribution in mice was studied, and mouse tumor models with primary tumor or lung metastasis were imaged in microPET. Competition assays against cold form [19F]M508F and CXCL12 showed that [19F]M508F or CXCL12 blocked [18F]M508F binding to CXCR4 in a dose-dependent manner. In 30 minute post-injection microPET imaging, [18F]M508F-PET images of an orthotopic SCCHN animal model and an experimental animal model for lung metastasis of SCCHN exhibited fast blood clearance and significant uptake of [18F]M508F in the primary tumor as well as in the lung metastases.

To date, several CXCR4 antagonists have been developed. Fujii's group at Kyoto University pioneered development of a series of peptide analogs that exhibited excellent potency against CXCR4. An attempt to label a peptidic antagonist for single photon emission computed tomography (SPECT) with In-111 showed that the blood clearance was too slow for 18F-PET. Currently, [64Cu]AMD3100, a metal-chelating bicyclam, is the only reported PET tracer for CXCR4 imaging. [18F]M508F reported here has a CXCR4 binding affinity over 50 times better than [64Cu]AMD3100. So far, we have finished toxicity studies in macaque monkeys and we are in a process of eIND filing for clinical translation. As the first CXCR4-detecting [18F]PET tracer, [18F]M508F has a great potential to become a clinical imaging agent for prediction and early detection of SCCHN metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5227. doi:10.1158/1538-7445.AM2011-5227