General principles of biological imaging. (a) Enzymes as reporter genes; upon expression of the reporter gene, the imaging marker (M) that can freely cross the plasmic membrane is metabolised within the cell (the most commonly used enzymatic reaction is a phosphorylation). As a result, the phosphorylated marker becomes incapable of recrossing the plasmic membrane and is trapped within the cell. (b) Receptors as reporter genes; upon expression of the reporter gene, the imaging ligand (L) binds to its receptor, resulting in the accumulation of the detectable ligand in the transduced tissue. This signal can be amplified when the receptor gets internalised. (c) Transporter as reporter genes; upon expression of the transporter, the imaging compound (C) is selectively transported into the cell where it concentrates. Depending on its nature, the imaging tracer is either trapped into the cell, or released when the extracellular concentration decreases (question mark), leading to a transient signal.