Molecular imaging is a relatively new discipline, which developed over the past decade, initially driven by in situ reporter imaging technology. Noninvasive in vivo molecular imaging developed more recently and is based on magnetic resonance and nuclear (positron emission tomography; gamma camera) and in vivo optical imaging systems. Molecular imaging has its roots in both molecular biology and cell biology, as well as imaging technology. Most current in vivo molecular imaging strategies are "indirect" and involve the coupling of a "reporter/marker gene" with a complimentary "reporter/marker probe." Imaging the level of probe accumulation provides indirect information related to the level of reporter gene expression. Reporter gene constructs are driven by upstream promoter/enhancer elements that function as an "on/off switch"; they can be constitutive, leading to continuous transcription to identify the site and monitor the level and duration of gene (vector) activity. Alternatively, they can be inducible, leading to controlled gene expression, or they can function as a sensor element to monitor the level of endogenous promoters and transcription factors. Three indirect strategies for imaging therapeutic transgenes are discussed. Several examples of imaging endogenous biological processes in animals using reporter constructs, radiolabeled probes, and positron emission tomography imaging are reviewed (p53-dependent gene expression, T-cell receptor-dependent activation of T-lymphocytes, and trafficking of T-lymphocytes). Issues related to the translation of noninvasive molecular imaging technology into the clinic are discussed.
