Design， Synthesis， and Evaluation of a Neurokinin-1 Receptor-Targeted Near-IR Dye for Fluorescence-Guided Surgery of Neuroendocrine Cancers.

The neurokinin-1 receptor (NK1R) is implicated in the growth and metastasis of many tumors， including cancers of the brain (e.g.， gliomas， glioblastomas， and astrocytomas)， skin (e.g.， melanomas)， and neuroendocrine tissues (cancers of the breast， stomach， pancreas， larynx， and colon). Because overexpression of NK1R has been reported in most of these malignancies， we have undertaken designing an NK1R-targeted near-infrared (NIR) fluorescent dye for fluorescence-guided surgeries of these cancers. We demonstrate here that an NK1R-binding ligand linked to the NIR dye LS288 selectively accumulates in NK1R-expressing tumor xenografts with high affinity (Kd = 13 nM)， allowing intraoperative imaging of these cancers in live mice. Because tumor accumulation is nearly quantitatively blocked by excess unlabeled ligand， and because NK1R-negative tumors and normal tissues display virtually no uptake， we conclude that the observed tumor retention is NK1R-mediated. Results on the synthesis， in vitro characterization， and animal testing of NK1R-targeted NIR dye are presented.