Quantifiable Lung Imaging
Diffuse lung diseases, such as emphysema and pulmonary fibrosis, are very difficult to quantify. Historically, histological sections were used, but unless the entire lung is sliced, quantification can be hampered.
“Improvements in CT devices allow imaging of soft tissues, like the lungs, with fairly good resolution,” explained Lawrence de Garavilla, Ph.D., scientific director and fellow, imaging and PK/PD, immunology research, Janssen Research and Development. “With our micro-CT unit we can get in vivo resolution of 45–50 µm and in ex vivo studies, using a contrast agent, 5 µm. This allows us to look at alveoli, the terminal structures in the lung where gas exchange occurs.
“CT imaging allows us to image the whole lung, create a 3D rendering, and quantify the amount of fibrosis. It is a big change; we now have an objective quantifiable technique. Instead of having a pathologist sit at a microscope and subjectively analyze 50–100 lung slides, the resolution of our assay and the robustness of this imaging technique allow determination of, and differentiation between, 5 and 10% degree of fibrosis.”
Measuring efficacy during pulmonary drug clinical trials is very difficult. Functional tests, such as spirometry, are used but are crude measures of airway inflammation, fibrosis, and emphysema. Imaging techniques could prove to be a valuable clinical tool to quantify the degree of lung disease and improvement with novel therapeutics.
Looking forward, CT imaging may also be applicable as a noninvasive clinical diagnostic tool, especially for airway inflammation. Currently, bronchoscopies are performed but only on a limited basis since they are invasive and provide incomplete diagnostic information.
Dr. de Garavilla envisions using lung imaging to track the number and different types of inflammatory cells, to differentiate which cells are going into the lungs and the therapeutics’ effects on the various cell types.
Tracking Molecules and Diseases
PET tracers can be target- or disease-based. “Target-based PET tracers are used to determine that you have the desired characteristics of the pharmacological molecule. This is an essential step in developing a molecule and being able to take it into proof-of-mechanism or proof-of-concept studies,” said Aidan Power, M.D., vp and head, pharmatherapeutics, precision medicine, Pfizer Worldwide Research and Development.
“Let’s say a compound must bind to 80% of a particular receptor in the brain to be efficacious. We need to use a tracer so we can understand the percent of occupancy of the receptor. That is why there is a specific need to develop PET tracers for specific receptors.”
Required properties for the target-based tracers depend on where they will go in the body. PET tracers that need to go into the brain must have a molecular weight less than 600 and be moderately lipophilic. Target-based tracers must be highly specific, have high affinity, accumulate in target-rich tissues, and clear rapidly from others.
“There is also a lot of interest in developing PET tracers for disease processes. The amyloid-plaque tracers are disease-based, not specific to a particular drug, and may well be used for diagnosis in the future. At least you have it reasonably narrowed down that you have a strong clinical suspicion that someone has a disease. It is possible you might use them to evaluate how well someone is responding to treatment,” continued Dr. Power.
“We are going to continue to see a lot of development in tracers to help us diagnose and understand disease. These are significant advances that will require a lot of science. It is not so much about the specifics of the technology as much as about how we will be able to systematically apply it.”
The Cheap Man’s PET
Cerenkov radiation is the familiar blue glow one sees coming from a pool of water in a nuclear reactor.
In 2009, using a modern ultra-cooled CCD technology, the first Cerenkov emission from a subcutaneous tumor after in vivo administration of the commonly used PET tracer 18F-FDG was recorded. Data showed accumulation of the tracer in tumor-bearing animals by imaging its optical signal, rather than its nuclear decay signature.
While bioluminescence is a chemical reaction that creates light, CR is light produced at the quantum level.
“If we look at the nuclear decay of beta+ or beta- events, one of the things released is a charged particle. As the charged particle interacts with the local medium it polarizes the surrounding area, and after it passes, the area relaxes back to its normal state. During this transition CR is produced. Light is the resulting output,” explained Robbie Robertson, scientist I, biomedical imaging group, Millennium: The Takeda Oncology Company.
Unlike PET, which measures an annihilation event that creates gamma rays, CR is produced along the entire path length of the charged particle.
“Our throughput capacity of Cerenkov luminescence imaging (CLI) is approximately 10-fold greater than traditional PET imaging. Plus, within a few hours of training, anyone can run a CCD system.”
“One of CLI’s greatest advantages lies in its ability to allow a company to quickly screen through a large amount of radiolabeled compounds in a shorter timeframe than is currently achievable with preclinical PET imaging systems. This frees up time on PET scanners and allows them to be used to produce the required higher quality data for future transition of a drug from the preclinical to the clinical setting,” concluded Robertson.
Affectionately referred to as “The Cheap Man’s PET”, the number of articles referencing CLI since 2009 illustrates the modality’s acceptance.