aminopyridazine and dihydrotetrabenazine

Our research groups recently described a series of small-molecule inducers of β-cell proliferation that could be used to increase β-cell mass. To mitigate the risk of nonspecific proliferation of other cell types, we devised a delivery strategy built on the tissue specificity observed in the experimental β-cell imaging agent (+)-dihydrotetrabenazine (DTBZ). The β-cell proliferator agent aminopyrazine (AP) was covalently linked with (+)-DTBZ to afford conjugates that retain both the proliferation activity and binding affinity for vesicular monoamine transporter-2 (VMAT2). In vivo mouse tissue distribution studies of a prototypical AP-DTBZ conjugate showed 15-fold pancreas exposure over plasma. Tissue-to-plasma ratios in liver and kidneys were two- and five-fold, respectively. This work is the first demonstration of enhanced delivery of β-cell-proliferating molecules to the pancreas by leveraging the intrinsic tissue specificity of a β-cell imaging agent.

Topics: Animals; Cell Line; Cell Proliferation; Chromatography, High Pressure Liquid; Drug Carriers; Insulin-Secreting Cells; Kidney; Liver; Mice; Mice, Inbred BALB C; Pancreas; Pyridazines; Rabbits; Tandem Mass Spectrometry; Tetrabenazine; Tissue Distribution; Vesicular Monoamine Transport Proteins