Optimized Near-IR Fluorescent Agents for in Vivo Imaging of Btk Expression

Bruton’s tyrosine kinase (Btk) is intricately involved in anti-apoptotic signaling pathways in cancer and in regulating innate immune response. A number of Btk inhibitors are in development for use in treating B-cell malignancies and certain immunologic diseases. To develop robust companion imaging diagnostics for in vivo use, we set out to explore the effects of red wavelength fluorochrome modifications of two highly potent irreversible Btk inhibitors, Ibrutinib and AVL-292. Surprisingly, we found that subtle chemical differences in the fluorochrome had considerable effects on target localization. Based on iterative designs, we developed a single optimized version with superb in vivo imaging characteristics enabling single cell Btk imaging in vivo. This agent (Ibrutinib-SiR-COOH) is expected to be a valuable chemical tool in deciphering Btk biology in cancer and host cells in vivo

Design, Synthesis, and Evaluation of a Low-Molecular-Weight ¹¹C‑Labeled Tetrazine for Pretargeted PET Imaging Applying Bioorthogonal in Vivo Click Chemistry

A low-molecular-weight tetrazine labeled with the short-lived positron emitter carbon-11 was developed as a bioorthogonal PET probe for pretargeted imaging. A method for efficient and fast synthesis of this imaging agent is presented using radiolabeling of a readily available precursor. High reactivity with <i>trans</i>-cyclooctenes was observed and in vivo investigations including PET/MR scanning showed homogeneous biodistribution, good metabolic stability, and rapid excretion in naive mice. These properties are key to the success of bioorthogonal ¹¹C-PET imaging, which has been shown in a simple pretargeting experiment using TCO-modified mesoporous silica nanoparticles. Overall, this ¹¹C-labeled tetrazine represents a highly versatile and advantageous chemical tool for bioorthogonal PET imaging and enables pretargeting approaches using carbon-11 for the first time

Isolation and Structure Elucidation of Pentahydroxyscirpene, a Trichothecene <i>Fusarium</i> Mycotoxin

Pentahydroxyscirpene, a novel trichothecene-type compound, was isolated from <i>Fusarium</i>-inoculated rice. The structure of pentahydroxyscirpene was elucidated by 1D and 2D NMR spectroscopy and X-ray single-crystal diffraction. The conformation in solution was determined by NOESY experiments supported by quantum chemical calculations. <i>In vitro</i> toxicity tests showed that pentahydroxyscirpene inhibits protein synthesis as do other trichothecenes

Isolation and Structure Elucidation of Pentahydroxyscirpene, a Trichothecene <i>Fusarium</i> Mycotoxin

Pentahydroxyscirpene, a novel trichothecene-type compound, was isolated from <i>Fusarium</i>-inoculated rice. The structure of pentahydroxyscirpene was elucidated by 1D and 2D NMR spectroscopy and X-ray single-crystal diffraction. The conformation in solution was determined by NOESY experiments supported by quantum chemical calculations. <i>In vitro</i> toxicity tests showed that pentahydroxyscirpene inhibits protein synthesis as do other trichothecenes