Innovation Delivered
This article was published in discovered, The HZDR Research Magazine (Issue 02.2013, December 2013/January 2014, ISSN: 2194-5713; PDF 2.2MB)
Six white CD-1 mice are scurrying through the litter in their cage, climbing the metal bars, nibbling away at the pellets they are being fed, and snuggling with each other. What they don't yet know is they're about to participate in a pivotal study. One that will save lives - those of mice and, one day, of men. As part of his dissertation, Mathias Kranz, Ph.D. student at the HZDR Research Site Leipzig, is currently investigating the degree of radioactivity that builds up within the bodies of mice whenever radioactive probes - called radiotracers - are used, and identifying in which organs specifically it accumulates. Eventually, these data will be extrapolated to the human magnitude. Radiotracers are chemical compounds that include a radioactive element of some sort, which can help scientists observe metabolic processes in living organisms.
Specifically, in the case of the Leipzig project, we're talking about the two radiotracers [18F]fluspidine and [18F]flubatine - both of them molecules containing the radionuclide 18F (fluorine). They're supposed to ultimately find their way into the diagnostics of cancers and neurodegenerative diseases like Alzheimer's. Key is their ability to imitate properties of various endogenous structures.
Before a radioactive probe is ready for use in the hospital setting, its efficacy and safety must first be documented in living organisms.
Once injected into the human body, they bind with high affinity to certain targets - in the case of the "PET sugar" [18F]FDG, which is also used at the Leipzig site, highly metabolically active tissues like tumors. The emitted radiation from the radioactive molecules can be captured and subsequently analyzed using positron emission tomography (PET). However, before a radioactive tracer can be introduced into the hospital setting, its efficacy and safety to the living organism must first be confirmed. This is a prerequisite imposed by the German Federal Office for Radiation Protection (BfS) and the Federal Institute for Drugs and Medical Devices (BfarM). This multistep procedure starts with work on mice and occasionally pigs and ultimately leads to research conducted on healthy human subjects. Here, the HZDR scientists are receiving support from their colleagues at the Clinic for Nuclear Medicine at Leipzig University Hospital.
Leipzig as reference site
As of spring 2013, when operations by experienced colleagues at the HZDR main site Dresden first commenced, Germany's first-ever commercial full-body PET/MRI for small animals opened in Leipzig - one of only a few worldwide. The HZDR is the reference site for Hungarian manufacturer Mediso (Budapest) - which brings with it a number of obvious benefits: "There are still a handful of delayed-onset childhood illnesses but whenever we do report any problem, help typically arrives within a matter of hours," Mathias Kranz explains. The 27-year-old fellow, who holds a master's in engineering, studied biomedical technology at Ilmenau University of Technology, and has been working at the HZDR Institute of Radiopharmaceutical Cancer Research for about a year now. He is thrilled with the new device: "Not only does it allow us to obtain information about metabolic processes that are happening inside the body, it also yields high-resolution three-dimensional images that document the exact location and distribution of soft tissues." especially when it comes to brain imaging, MR devices yield far better results than conventional PET and computer tomography (CT) combinations.
The mice remain safe
"Without these methods, we would need to dissect the animal subjects, remove individual organs, and then measure them in order to determine the degree of radioactivity that has accumulated in the body following injection of the radiotracer. What's interesting is not only the current dose rate but also how it changes over the course of minutes and hours, which helps determine the organ dose. Thanks to PET/MRI, we're able to conduct even long-term studies using the same exact mouse," Mathias Kranz explains. In the case of other methods, one laboratory animal has to be sacrificed each time a single measurement is obtained.
During examination, the mice are lying on a heated animal bed, their breathing monitored with the help of a pressure sensor. The radioactively labeled substance is injected into the tail vein. The mice are fully anesthetized and won't remember anything afterwards. On a screen, Mathias Kranz is now examining a black and grey image showing the inside of the mouse's body. Red, yellow, and blue spots are lighting up in certain body regions. "Red means these are sites where there is a high degree of radioactivity, in other words that a lot of our substance was deposited in these places," the young scientist explains. At first glance, the liver, kidneys, and bladder are easily recognized - organs, which are actively involved in the substance's elimination from the body.
After the experiments are done, Mathias Kranz calculates the expected effective human dose. This serves as a risk-assessment at the time of introducing the probes into the clinical setting. Based on their results, the researchers have filed for approval of a study with the BfS for use of their newly developed radiotracers (+)-[18F]flubatine and (S)-(-)-[18F]fluspidine in humans. The scientists are working closely with their colleagues at Leipzig University Hospital, Department of Nuclear Medicine, on these projects. The projected start date is early 2014.
