Accelerating the development of novel molecular imaging probes: a role for high-throughput screening

Abstract

Molecular imaging is a rapidly emerging research tool and clinical discipline aimed at noninvasive, quantitative visualization of in vivo molecular processes occurring at cellular and subcellular levels. At present, advancement of the molecular imaging field is driven by the development of improved imaging hardware for use in preclinical and clinical settings, the identification and validation of new, biologically relevant imaging targets, and the development of improved imaging probes derived from novel chemistries. Of these 3 essential facets, which comprise a majority of current molecular imaging research, hardware development and novel target discovery significantly outpace the development and clinical advancement of new molecular imaging probes, particularly with respect to cancer imaging.

FIGURE 1

Schematic illustration showing various attributes of HTS models. Adapted from (7).

FIGURE 2

Screening of small-molecule library for antiangiogenic compounds with transgenic zebrafish. (A) Bright-field and fluorescent images of 2-d–postfertilization zebrafish treated with vehicle control or PTK787 at 10 μmol/L (positive control). Angiogenic blood vessel growth was inhibited in head and trunk of PTK787-treated embryos. (B) For quantification of vessel growth in embryos, trunk was manually isolated from fluorescent image. Automated algorithm counted intersegmental vessels (IV) and various branching arteries. DLAV = dorsal longitudinal anastomotic vessel; VA = vertebral artery. (C) LOPAC1280 library was collaboratively screened by Zygogen (blue points) and Emory University (green points). Positive hits (red points) were defined as compounds that caused inhibition of angiogenic vessel count by more than 3 SDs from plate average. (Reprinted with permission of (13).)