In vivo target recognition with high-resolution imaging: significance for drug development

In vivo target identification is basic for understanding mechanisms of drug action. Target identification requires cellular resolution. Extrapolation from blood bioavailability, low-resolution scans, radioassays, or in vitro tests regularly produce false-negatives and false-positives. Common ADME procedures disrealize organ complexities. While low-specificity high-capacity sites of deposition are easily recognized, high-specificity low-capacity receptor sites remain hidden. Serious limitations of target recognition are revealed in comparative studies with three methods: high-resolution microscopic autoradiography, radioassay, and whole-body autoradiography. With radioassays and whole-body autoradiography, many targets are simply undetectable. For example, high-resolution microscopic target information for vitamin D, gained 20-30 years ago, was widely ignored. The narrow calcium focus for this multi-target and multi-function hormone was perpetuated until recently through deficient results from conventional assays together with related expert bias. Thus, follow-up has been delayed on discoveries from the use of unconventional histopharmacology methods, pointing at important actions and therapies beyond systemic calcium regulation. High-resolution 'in vivo' target identification with associated functional characterization is useful not only for understanding mechanisms of action, but also for providing leads for innovative and successful drug development and prediction.