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EXAMINATION ELECTIVE COURSE MOLECULAR IMAGING 2006
Question 1
The concept of molecular imaging is rapidly gaining importance in biomedical research and
clinical diagnostics.
A. What are the main advantages of molecular imaging as compared to traditional imaging
techniques? Give at least three reasons and motivate your answer.
B. Describe the strategy with which a new target for molecular imaging can be identified.
C. Apoptosis is a form of programmed cell death. Describe the morphological and
biochemical characteristics of apoptosis.
D. Explain what the caspase cascade is.
E. Phosphatidylserine (PS) is an aminophospholipid, which is present in all cells. Explain why
PS is suitable for molecular imaging and why PS is a better target for molecular imaging than
activated caspase-3.
Question 2
Ultrasound traditionally plays an important role in medical diagnostics. In recent years it is
also being developed for molecular imaging and therapeutic applications.
A. Diagnostic ultrasound is carried out at circa 3 MHz.
a. Briefly explain the principles of the ultrasound technique.
b. What is the propagation speed of the sound waves?
c. What is the spatial resolution of a typical diagnostic ultrasound instrument?
B. In ultrasound, gas bubbles with a diameter of circa 3 micrometer are used in several
applications.
d. What is the reason that individual gas bubbles can be detected by ultrasound,
although the bubbles are significantly smaller than the resolution of the
technique?
e. The resolution of ultrasound is lower than the average size of mammalian
cells. Describe how ultrasound can nevertheless be used for molecular
imaging purposes.
Question 3
The paper by Mulder et al. (Nano Letters, 2006; see copy) describes the development of
quantum dots for molecular imaging with MRI and optical techniques.
A. Give at least 3 reasons why targeted MRI contrast agents, in the early phase of
development, are also equipped with a label for detection with optical techniques.
B. On the basis of which criteria did the authors conclude that the new quantum dot
preparation is suitable for molecular imaging of biological markers with MRI?
C. Briefly describe the evidence that the authors provide in the paper for the specificity
of the interaction of RGD-conjugated quantum dots with endothelial cells.
D. Briefly describe, whether you think that quantum dots could be used for molecular
imaging in human patients in the future.
Question 4
Atherosclerosis is at the basis of the most important cardiovascular disease processes. This
explains why a lot of effort is made to develop molecular imaging tools for the non-invasive
detection of the different stages of atherosclerosis.
A. Describe the most important stages in the process of atherosclerosis.
B. Indicate which cell you would like to image in which stage. Motivate your choice.
C. Describe also which molecular target you would like to use and why.
Question 5
Remodeling of the extracellular matrix plays a critical role in a number of important diseases,
including atherosclerosis and cancer. The same process also largely determines the
mechanical properties of tissue-engineered tissue. To monitor the formation of collagen in
tissue-engineered tissues, a collagen-specific probe that is based on the collagen binding
protein CNA35, was recently developed in Eindhoven. CNA35 was coupled to Oregon green
488, with the use of an amine-reactive succinimide group.
A. Oregon green 488 is one out of many synthetic pigments that are commercially
available. Mention three spectral properties that are important for the choice of a
fluorophore. Mention at least two other properties that should be considered when
choosing the optimal fluorescent group.
B. Apart from synthetic dyes, there are two other classes of fluorescent labels that are
often used for imaging: quantum dots and fluorescent proteins. Discuss the
advantages and disadvantages of these three kinds of compounds on the basis of the
following criteria: fluorescence intensity, availability of different colours, bioconjugation to targeting ligands, and size.
Matrix metallo-proteases play a critical role in extracellular matrix remodelling because these
proteases can degrade existing protein structures. Therefore, we would very much like to
develop a fluorescent sensor that is capable of measuring this protease activity.
C. Describe a fluorescent probe that can be used to detect protease activity in the
extracellular matrix. Indicate which of the above fluorophores (i.e., synthetic dyes,
quantum dots and fluorescent proteins) you consider most suitable for this purpose.
D. Describe the same sensor, except that it now should be able to measure intracellular
protease activity.
E. Explain why the above sensors are only suited for studies of isolated cells and
characterization of tissues, and not for imaging of animals and humans? Which
optical technique is most suited for the latter application?
Question 6
Nuclear techniques play an important role in the field of molecular imaging, for several
reasons.
A. Explain briefly the technology of SPECT.
B. You decide to accept a job with an imaging company. Your first job assignment is the
design of a time-of-flight PET for animals. Fortunately, you remember the speed of light to be
c=3x105 km/s and the diameter of a mouse to be ca. 3 cm.
- explain the concept of time of flight (with the help of a short drawing)
- how fast should the detection at least be to detect annihilation events in the mouse
based on time-of-flight?
Tracer technology plays a crucial role in the advancement of nuclear imaging techniques.
C. Explain briefly the mechanism behind the use of FDG (fluorodeoxyglucose) in PET,
answering the following points:
- the main path by which FDG uptake into the cell takes place
- why is FDG trapped in the cell?
- which step in the metabolic conversion of FDG is blocked?
D. FLT and FDG both are PET tracers that are used in cancer diagnostics.
- explain briefly the mechanism underlying the use of FLT tracers
- give an example, where FLT is superior to FDG and explain why that is the case.