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Non-nuclear molecular imaging

Non-nuclear molecular imaging consists of techniques that assess the cellular and physiological behaviour without using radioactive materials. These include:

  • Contrast-enhanced ultrasound
  • Optical imaging
  • MR spectroscopy. This is covered in the MRI chapter.

Contrast-enhanced ultrasound

Contrast-enhanced ultrasound (CEUS) involves the injection of microbubbles. Microbubbles are structures measuring 1 to 4 μm formed of a high-molecular-weight gas core, such as perfluorocarbons and sulphur hexafluoride, with a shell typically made of lipid. After injection, they circulate in the blood for a few minutes until they are removed by the reticuloendothelial system or are broken down naturally or by the ultrasound wave.

They are highly echogenic due to the impedance mismatch between the gas and blood / tissue. This non-targetted technique has been used to assess blood flow (e.g. in patent foramen ovale) and perfusion (e.g. liver tumours).

CEUS in molecular imaging

More recently, ligands are being added to the shells to turn them into molecular imaging agents i.e. they will bind to specific molecular targets. As the ultrasound bubbles are relatively large they are limited to vascular targets. The current targets undergoing research are angiogenesis markers (e.g. VEGF), inflammatory markers (e.g. ICAM-1) and thrombosis markers (e.g. GPIIb-IIIa).

Although CEUS is in common use clinically, targeted CEUS in which ligands have been added to the shell of the bubbles is still in the pre-clinical stages.


  • No radiation
  • Rapid acquisition of images
  • Real-time scanning
  • Simple equipment


  • Microbubbles are short-lived
  • Can only scan small areas
  • Very operator dependent

Optical imaging

Optical imaging utilises processes that produce visible photons that can then be detected and measured. The two main techniques are bioluminescence and fluorescence.


  • No radiation
  • In fluorescence the signal can be repeatedly obtained
  • Rapid acquisition of images
  • Real-time imaging


  • Low background signal
  • Scatter of released photons
  • Limited depth of penetration of the photons i.e. only suitable for superficial structures


Bioluminescence imaging utilises biochemical reaction of the enzyme luciferase in which optical photons are created. Luciferin is injected and, when it enters a cell containing the enzyme luciferase, a chemical reaction occurs in which a detectable photon is produced. Cells that typically contain luciferase are tumour cells making bioluminescence useful for detecting the presence of tumour cells and response to therapy.


In fluorescence the injected molecule is activated with an external light source of appropriate wavelength and then the photon emissions released from the decay of the excited state are measured. The advantage of fluorescence is that the molecules can be repeatedly excited (to a limit) to keep measuring a signal.

Written by radiologists, for radiologists with plenty of easy-to-follow diagrams to explain complicated concepts. An excellent resource for radiology physics revision.

Σ  Summary

  • Non-nuclear molecular imaging consists of:
    • Molecular targeted imaging without the use of radiation
  • Contrast-enhanced ultrasound
    • Microbubbles 1-4 μm filled with perfluorocarbons and sulphur hexafluoride with a lipid shell
    • Research into attaching ligands to shells for molecular targeting
    • Advantages: quick, easy to use equipment, real-time
    • Disadvantages: very operator dependent, can only scan small areas, microbubbles short-lived
  • Optical imaging
    • Detectable photons released which create the image
    • Two types:
      • Bioluminescence: luciferin injected which is broken down by luciferase enzyme in cancer cells and releases detectable photons
      • Fluorescence: Molecules activated with light and release detectable photons with the excitable state decays
    • Advantages: quick, real-time imaging, in fluorescence molecules can be repeatedly excited
    • Disadvantages: low background signal, limited depth of penetration of released photons, photons scatter
  • MR spectroscopy