The natural products colchicine and combretastatin A-4 (CA4) are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of a 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI50 = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC50 = 1.1 µM) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCID mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent (VDA) that may prove useful for the treatment of cancer.

Synaptic vesicle glycoprotein 2A (SV2A) is a 12-pass transmembrane glycoprotein ubiquitously expressed in presynaptic vesicles. In vivo imaging of SV2A using PET has potential applications in the diagnosis and prognosis of a variety of neuropsychiatric diseases, e.g., Alzheimer's disease, Parkinson's disease, schizophrenia, multiple sclerosis, autism, epilepsy, stroke, traumatic brain injury, post-traumatic stress disorder, depression, etc. Herein, we report the synthesis and evaluation of a new 18 Flabeled SV2A PET imaging probe, [ 18 F]SynVesT-2, which possesses fast in vivo binding kinetics and high specific binding signals in non-human primate brain.

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Kappa opioid receptor (KOR) antagonists are potential drug candidates for diseases such as treatment-refractory depression, anxiety, and addictive disorders. PET imaging radiotracers for KOR can be used in occupancy study to facilitate drug development, and to investigate the roles of KOR in health and diseases. We have previously developed two C-labeled antagonist radiotracers with high affinity and selectivity toward KOR. What is limiting their wide applications is the short half-life ofC. Herein, we report the synthesis of a first F-labeled KOR antagonist radiotracer and the initial PET imaging study in a nonhuman primate.

Conflict of Interest Statement: JEH has related IP and equity interest in and receives consulting fees in the form of equity options from Patrys Ltd, a biotechnology company that has licensed IP that is the basis of this work. ZR, VD, JAC, JZ, and JEH are inventors on IP related to DX1. JZ receives consulting fees in the form of equity options from Patrys Ltd. VD and JAC are employees of and have equity interest in Patrys Ltd. The remainder of the authors declare no competing interests.