Molecular imaging is often thought to be a highly specialised technique that is more applicable to research than everyday clinical practice. Contrary to this perception, there are many imaging techniques in widespread use that have been shown to correlate with particular biomolecular events (Fig. 1). For example, the degree of enhancement of lung nodules on CT correlates with the expression of vascular endothelial growth factor (VEGF), a molecule that stimulates tumour angiogenesis. Uptake of radio-iodine in thyroid tumours, one of the oldest techniques in nuclear medicine, results from expression of the sodium-iodide symporter molecule on the tumour cell surface. Other examples from nuclear medicine are illustrated in Fig. 1.
FIGURE 1 ■ Examples of 'everyday' molecular imaging. (A) Peak contrast enhancement of a lung nodule (arrow) on CT correlates with expression of vascular endothelial growth factor (VEGF). (B) Uptake of radioiodine (131I) in miliary lung metastases (arrowheads) of thyroid cancer reflecting expression of the sodium/iodide (Na+/I–) symporter. (C) Uptake of 111In-octreotide in a pelvic carcinoid tumour (arrow) indicates expression of somatostatin receptors. (D) Uptake of 18F-fluorodeoxyglucose (FDG) in multiple metastases due to expression of Glut-1 glucose transporters.
The imaging strategies capable of assessing molecular and genetic processes can be classified as direct, surrogate or indirect:
• Direct molecular imaging involves direct interaction between the imaging probe and the molecular target (e.g. a specific enzyme or receptor).
• Surrogate molecular imaging reflects the downstream physiological effects of one or more molecular or genetic processes.
• Indirect molecular imaging strategies are more complex, typically involving reporter gene approaches in which cellular function is modified so that the target gene induces a molecular change that can be assessed with a complementary imaging probe. Reporter gene imaging is summarised in Fig. 2.
FIGURE 2 ■ Summary of the imaging reporter gene concept. The reporter gene is incorporated into the nuclear DNA of the target cells by transfection (e.g. viral vector). If the reference gene is active, the cell translates the reporter gene to produce reporter messenger RNA (mRNA) which is translated to the reporter protein. The reporter substrate interacts with the reporter protein to produce an imaging signal (e.g. gamma ray, paramagnetic effect).
The reporter gene comprises a length of deoxyribonucleic acid (DNA) which is introduced into the target cells by transfection using, for example, a viral vector. The reporter gene can be designed so that it is activated by one of a range of genetic or molecular processes of interest. The activated reporter gene is transcribed into the corresponding messenger ribonucleic acid (mRNA) which is, in turn, translated to the reporter protein. Subsequent administration of a reporter substrate that interacts with the reporter protein produces an imaging signal. A frequently used reporter gene is the herpes simplex virus type 1 thymidine kinase (HSV1-TK), which has radiolabelled substrates (e.g. fluorodeoxy-arabinofuranosyl-iodouracil, or FIAU) that can be labelled with iodine-123 for single photon emission tomography or iodine-124 for PET.44 MR-based reporter genes include those encoding for a modified human transferrin receptor that increases the signal on MR imaging due to binding of supra-paramagnetic iron compounds.45 Another MR reporter gene produces β-galactosidase for which a special gadolinium contrast agent (EgadMe) acts as substrate.46 Access of water to the gadolinium is blocked unless the contrast molecule is cleaved by β-galactosidase, thereby producing contrast enhancement on MR.
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