Synthesis, Stability and Relaxivity of TEEPO-Met: An Organic Radical as a Potential Tumour Targeting Contrast Agent for Magnetic Resonance Imaging

Abstract

Cancer is a widespread and life-threatening disease and its early-stage diagnosis is vital. One of the most effective, non-invasive tools in medical diagnostics is magnetic resonance imaging (MRI) with the aid of contrast agents. Contrast agents that are currently in clinical use contain metals, causing some restrictions in their use. Also, these contrast agents are mainly non-specific without any tissue targeting capabilities. Subsequently, the interest has notably increased in the research of organic, metal-free contrast agents. This study presents a new, stable organic radical, TEEPO-Met, where a radical moiety 2,2,6,6-tetraethylpiperidinoxide (TEEPO) is attached to an amino acid, methionine (Met), as a potentially tumour-targeting moiety. We describe the synthesis, stability assessment with electron paramagnetic resonance (EPR) spectroscopy and relaxation enhancement abilities by an in vitro nuclear magnetic resonance (NMR) and phantom MRI studies of TEEPO-Met. The new compound proved to be stable notably longer than the average imaging time in conditions mimicking a biological matrix. Also, it significantly reduced the relaxation times of water, making it a promising candidate as a novel tumour targeting contrast agent for MRI.

Human Serum Albumin Labelled with Sterically-Hindered Nitroxides as Potential MRI Contrast Agents

“…The plots of the 1 H relaxation rate of water (1/T 1 ) versus the nitroxide concentration were linear for all agents, indicating the absence of aggregation ( Figure S7.1). The per-nitroxide r 1 values ranged from 0.33 to 0.51 mM −1 s −1 (Table 4), making them comparable to those reported in various nitroxide-bound polymers and dendrimers [15,29] and higher than for potential low-molecular-weight, nitroxide-based MRI probes at 7 T [20,21]. Moreover, per-nitroxide r 2 values ranged from 4.7 to 7.2 mM −1 s −1 , much greater than what is typical for individual nitroxides in solution; e.g., 2 has r 1 and r 2 of 0.15 and 0.17 mM −1 s −1 , respectively [76].…”

“…The r2/r1 values of 10.4-14.3 obtained in a 7 T magnetic field suggest that at high field strengths the conjugates may work most effectively as T2 contrast agents [15,19]. The r2/r1 values per nitroxide exceed those of most other nitroxide-based ORCAs [15,20,23] and the r1 relaxivities are similar to values at 7 T for other ORCAs.…”

Brain Redox Imaging Using In Vivo Electron Paramagnetic Resonance Imaging and Nitroxide Imaging Probes

“…Other imaging modalities such as MRI should be used with EPR imagers. Lastly, development of novel nitroxide imaging probes is needed for medical imaging studies [54]. BBB-permeable, nontoxic nitroxide imaging probes are necessary for brain redox studies.…”

Assessment of the Relaxation-Enhancing Properties of a Nitroxide-Based Contrast Agent TEEPO-Glc with In Vivo Magnetic Resonance Imaging

“…However, nitroxides with bulky side groups have shown remarkable stability in conditions mimicking biological matrix [23,24]. e research of nitroxide-based contrast agents comprises both macromolecular [25][26][27][28][29][30][31] and small molecule [32][33][34][35][36] systems. It is often considered that the advantage of using polymers or nanomaterials as a backbone for nitroxides is the possibility to attach several radical centers to the contrast agent molecule.…”

“…Our study has focused on attaching a highly stable nitroxide, TEEPO (2,2,6,6-tetraethylpiperidin-1-oxyl), to natural compound moieties that can potentially act as targeting units [35,36]. e method is commonly applied in the use of radiopharmaceuticals as tracers in PET (positron emission tomography) imaging [37].…”