The AlternativesToGd project is developing a new type of contrast agent for MR imaging, which is metal-free and completely cleared from the body, circumventing potential health concerns of conventional gadolinium-based contrast agents.
The European Medicines Agency (EMA) recently issued a recommendation to suspend three widely used magnetic resonance imaging contrast agents that are gadolinium (Gd)-bearing, and the U.S. Food & Drug Administration (FDA) has required new class warnings for such agents. Although these decisions were based on the absence of clinical evidence, they relate to potential major health concerns resulting from observed long-term accumulation of Gd in patient bodies. New findings documenting traces of Gd left in human tissues after repeated contrast-agent enhanced MRI are frequently reported in the literature.
This sends a clear message to carefully consider the necessity of each contrast injection in individuals undergoing an MRI scan. However, for a number of diagnostic procedures such as tumour characterisation, the use of a contrast agent is often essential. The accumulation of Gd in different organs, including the brain, and its unknown long-term effects, signal a definite medical need to seek radically new alternatives to conventional contrast agents.
The EU-funded AlternativesToGd sets out to identify and validate such radically new compounds as alternatives to conventional Gd-bearing contrast agents. The new class of MRI contrast agents will be metal-free, safe, and can be completely eliminated from the human body after the MRI exam.
The agents will consist of small endogenous molecules, in which nuclear spins are hyperpolarised to ensure high sensitivity to MR detection, even at very low doses. These agents will be labelled with stable-isotopes and thus avoid any ionising radiation that is associated with nuclear medicine methods. Furthermore, the hyperpolarised contrast agents will be of small molecular weight, inert, and with a bio-distribution pattern similar to Gd-bearing contrast agents, i.e. predominantly in the vascular and extracellular spaces.
The project’s ultimate goal is to demonstrate the feasibility of replacing Gd-bearing contrast agents in at least one type of contrast-enhanced MRI examination – with the motivation to stimulate further research and development in academia and industry.
More specifically, the AlternativesToGd project is looking at the development of unique hyperpolarised agents via dissolution-dynamic nuclear polarisation (dDNP), as well as via parahydrogen-induced hyperpolarisation (PHIP) and hyperpolarisation techniques based on optical or DNP irradiation of nano-diamonds. Conversely, the project also will need to develop tailored MRI tools for optimal observation of the hyperpolarised agents in vivo.
Although the project aims to find at least one replacement for the currently used Gd-bearing contrast agents, the variety of systems that will be developed may open the route for innovative diagnostic procedures based on the administration of ‘cocktails’ consisting of two or more hyperpolarised molecules. The particular combination of decay times and bio-distribution properties may provide, in one shot, an in-depth characterisation of the tissue microenvironments that could be largely superior to what is currently achieved with the available contrast agents.
The use of hyperpolarised agents for perfusion imaging or tissue-retention imaging for diagnostic MRI is a new technology that does not exist today. AlternativesToGd will lay the foundation for such a technology by providing the contrast agents, the means to increase their MR signal, and the routes for MR imaging of these hyperpolarised signals on clinical MRI scanners.
The project kicked off on October 1, 2019 and will run for three years until September 30, 2022. For more information, visit the project’s website at www.alternativestogd.eu.
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