Quantification of whole-body distribution and speciation of gadolinium-based contrast agents by Y-86 PET/MRI

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Project summary/Abstract Gadolinium-based contrast agents (GBCAs) are critical for diagnostic radiology and are used in about 40% of all magnetic resonance imaging (MRI) examinations, representing over 12 million administrations in the US per year. GBCAs provide vital insight in detecting and staging different cancers, multiple sclerosis, aneurysms and vascular blockages. In patients with poor renal function a single GBCA administration can cause nephrogenic systemic fibrosis (NSF), a very painful and debilitating fibrosing condition in which gadolinium (Gd) deposits are found in the skin and internal organs. Patients with normal renal function are also prone to Gd retention and can experience NSF-like symptoms. Despite a switch to more chemically stable macrocyclic GBCAs, Gd has been detected in brain, bone, heart and liver from biopsy and autopsy tissue, but its clinical significance remains to be fully understood. A key issue is that we lack the ability to measure how much Gd remains in the body after imaging, where it is retained, and how it is trafficked. At the preclinical stage, new responsive GBCAs, whose relaxivity changes in response to a local stimulus like pH change, are emerging as powerful tools to interrogate the pathological microenvironment. However decoupling relaxivity change from concentration change in vivo has proven elusive, limiting the application of these responsive probes. I recently showed that yttrium-86 chelates are ideal surrogates for their corresponding GBCAs both in vitro and in vivo. 86Y PET / GBCA MR is a noninvasive, highly sensitive technique that quantitatively reports on the in vivo Gd concentration, distribution and speciation, and is readily translatable to humans. 86Y PET/MR enables the measurement of in vivo relaxivity which informs on Gd speciation and can be used to measure biochemical processes through the use of responsive MR probes. For example, extracellular pH (pHe) is a key marker of tumor metabolism that can inform on prognosis and treatment response. In this proposal I will use 86Y PET/MR to address three fundamental and unresolved questions surrounding existing and next generation GBCAs: 1) Is there a GBCA that is more effectively eliminated and would therefore provide a safety benefit? 2) What is the speciation, i.e. chemical and biological form(s), of the retained Gd and is there evidence of toxicity? And 3) can simultaneous 86Y PET/MR enable quantitative molecular imaging with a responsive MR probe, specifically measuring extracellular tumor pH with a pH-responsive MR probe. The output of this work will be the development of a quantitative PET/MR protocol to follow in vivo biochemical processes non-invasively. This research will provide me with vital training in PET/MR imaging, biology and pharmacokinetics, while leveraging my current skills in analytical, inorganic and radiochemistry.