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Rapidly Synthesized Radiolabeled PET Tracers with Improved Biological Characteristics

Technology #16-0078

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Researchers
Zibo Li
Managed By
Matthew Howe
Commercialization Manager 919.966.3929
Patent Protection
US Patent Pending 16/062,756

Background
Positron-emission tomography (PET) is a medical imaging technique that utilizes radiolabeled tracers to aid in disease diagnosis for oncology, neurology, cardiology, and infectious diseases. PET imaging allows for detailed characterization of physiological processes, such as metabolism and blood flow. Most often PET is utilized by oncologists for cancer diagnosis and identification of metastases throughout a patient’s body. A glucose analogue called fluorine-18 (F-18) fluorodeoxyglucose (FDG) is frequently used for identifying tumor tissue, as the tracer will label cells with a high rate of glucose uptake, such as cancer cells. A wide range of tumors can be identified with PET, such as brain, pancreatic, prostate, lymphoma, colorectal, thyroid, and lung. While F-18 is widely used and has characteristics that minimize toxicity and radiation exposure to patients, there are limitations to incorporate F-18 into complex molecules. These include a relatively short half-life, nucleophilicity of fluoride, and the low concentrations of F-18 that are used to ensure patient safety. While the low concentrations of F-18 are necessary for safety, this has delayed the development of novel classes of complex radiolabeled biomolecules. Recent advances in the past decade developed by the inventors and other groups, which use tetrazine-trans-cyclooctene ligation reactions to increase the speed of reaction rates when synthesizing radiolabeled tracers and importantly maintain a low concentration of F-18, has generated new compounds that can be used in a variety of applications, including PET imaging. This increased reaction rate is a key advantage over conventional methods.  

Technology Overview
Researchers in the Department of Radiology at the University of North Carolina at Chapel Hill, along with collaborators at the University of Delaware and the Institute of Applied Synthetic Chemistry, have developed novel radiolabeled tracers for PET imaging, termed 18F-sTCO (F-18 strained trans-cyclooctene). 18F-sTCO is synthesized through a novel ligation reaction that improves upon the traditional tetrazine-trans-cyclooctene ligation, by utilizing tetrazine with a conformationally strained trans-cyclooctene. This allows for the rapid assembly of complex radiolabeled biomolecules for PET imaging. The improved reaction rate is due to the increased reactivity of comformationally strained trans-cyclooctene, as compared to conventional trans-cyclooctene. 
In vivo studies in a mouse model of glioblastoma demonstrate the utility of 18F-sTCO to specifically accumulate in the tumor tissue, relative to other tissues with high metabolic activity, such as the liver, kidney, and muscles. At 4 hours post-treatment the tumor tissue had taken up about twice as much of the tracer, when compared to other tissues. Importantly, the 18F-sTCO tracer demonstrates improved in vivo characteristics, such as stability, systemic circulation, and tumor uptake, when compared to tracers synthesized using conventional tetrazine-trans-cyclooctene ligation methods.  


Benefits
This novel tracer demonstrates specificity for uptake in tumor tissue and improved in vivo characteristics over conventionally synthesized tracers. Utilization of conformationally strained trans-cyclooctene yields increased reaction rates, providing the opportunity for the synthesis of a new class of PET radiolabeled tracers, with improved biological characteristics, which were previously unavailable with conventional tetrazine-trans-cyclooctene ligation methods.


Applications
The 18F-sTCO tracer has the potential for clinical utility in PET imaging for cancer diagnosis and metastasis identification in glioblastoma patients. In addition to this application, 18F-sTCO has applicability in other tumor times and could be used more broadly in PET applications, such as neurology, cardiology, and infectious disease.

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