School of Natural Sciences and Mathematics Smart MRI Agents for Detecting Extracellular Events In Vivo: Progress and Challenges UT Dallas Author(s): W. Shirangi Fernando Andre F. Martins Rights: CC BY 4.0 (Attribution) ©2019 The Authors Citation: Parrott, Daniel, W. Shirangi Fernando, and Andre F. Martins. 2019. "Smart MRI Agents for Detecting Extracellular Events In Vivo: Progress and Challenges." Inorganics 7(2): art. 18; doi: 10.3390/inorganics7020018 This document is being made freely available by the Eugene McDermott Library of the University of Texas at Dallas with permission of the copyright owner. All rights are reserved under United States copyright law unless specified otherwise. inorganics Review Smart MRI Agents for Detecting Extracellular Events In Vivo: Progress and Challenges Daniel Parrott 1 , W. Shirangi Fernando 2 and Andre F. Martins 1,2,3,* 1 Department of Radiology, UT Southwestern Medical Center, Dallas, TX 75390, USA; [email protected] 2 Department of Chemistry, University of Texas at Dallas, Dallas, TX 75080, USA; [email protected] 3 Werner Siemens Imaging Center, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany * Correspondence: [email protected] or [email protected] Received: 3 January 2019; Accepted: 29 January 2019; Published: 9 February 2019 Abstract: Many elegant inorganic designs have been developed to aid medical imaging. We know better now how to improve imaging due to the enormous efforts made by scientists in probe design and other fundamental sciences, including inorganic chemistry, physiochemistry, analytical chemistry, and biomedical engineering. However, despite several years being invested in the development of diagnostic probes, only a few examples have shown applicability in MRI in vivo. In this short review, we aim to show the reader the latest advances in the application of inorganic agents in preclinical MRI. Keywords: MRI; contrast agents; paramagnetic agents; responsive sensors; smart sensors 1. Introduction Magnetic resonance imaging (MRI) has become one of the most powerful tools in clinical medicine, largely because it offers exquisite high-resolution anatomical images of soft tissues. Since its advent in the early 1980s, there has been an explosion in the number of exams performed in the United States; there are now millions performed each year. Early in the development of the MRI, the utility of contrast agents (CAs) to enhance image quality and increase diagnostic accuracy was recognized; in fact, clinical trials for the first agent began in 1982, with final approval being granted in 1988 to Magnevist [1]. MRI CAs produce contrast-enhanced images between normal and pathologic tissues, increasing diagnostic accuracy and vastly expanding the utility of MRI [2]. Most clinically available agents contain a lanthanide chelated within a macrocyclic or linear aminopolycarboxylate, and are tissue non-specific or relatively insensitive. Recent developments in contrast agent development have focused on ligand modification of the side chains of the macrocyclic ring, to allow tuning and physiologic targeting of the CAs. There are several classes of CAs, including T1, T2, T2ex, and chemical exchange saturation transfer (CEST) (Figure1). The most common clinically available agents are T1 and T2. T1 and T2 agents shorten both longitudinal and transverse relaxation times (T1 and T2) of protons in tissue water, thereby increasing signal intensity in T1-weighted images (positive enhancement) or reducing signal intensity in T2-weighted images (negative enhancement). The extent to which these agents influence the relaxation rate (1/T1 or 1/T2) of tissue water is defined as relaxivity (r1 or r2, respectively). The r1 relaxivity depends on many factors, including the relaxation time of the paramagnetic metal base (e.g., Gd3+ has a relatively long electronic relaxation times), the relatively fast water exchange between water from bulk solvent and water molecules reaching the inner sphere of the lanthanide ion, and the molecular motion, typically governed by the rotational correlation time (tR)[3–7]. High relaxivity allows lower concentration targets to be detected efficiently, as high relaxivity leads to increased signal Inorganics 2019, 7, 18; doi:10.3390/inorganics7020018 www.mdpi.com/journal/inorganics Inorganics 2019, 7, 18 2 of 21 Inorganics 2019, 7, 18 2 of 21 generation [4]. T1-agents, which comprise almost all of the current clinically approved CAs, utilize 3+ paramagneticsignal generation metal ions[4]. T and1-agents, mostly which contain comprise the almost lanthanide all of the metal current gadolinium clinically (Gdapproved) due CAs, to it is optimalutilize paramagnetic paramagnetic and metal physical ions and properties mostly contain that the yield lanthanide high relaxivities metal gadolinium [8]. The (Gd human3+) due to body it is composedis optimal of approximately paramagnetic 60%and physical water; therefore, propertiesT that1-weighted yield high images relaxivities give excellent [8]. The human anatomical body detailsis 3+ that cancomposed be boosted of approximately with the application 60% water; of therefore, the Gd T-based1-weighted contrast images agents give excellent (CAs) [9 ,anatomical10]. However, thesedetails CAs are that mainly can be non-specific, boosted with withthe application no tissue preference,of the Gd3+-based and no contrast dynamic agents response (CAs) to[9,10]. changes in physiology.However, these One CAs of theare mainmainly goals non-specific, in recent with years no tissue has preference, been to develop and no dynamic newer typesresponse of agentsto for measuringchanges in importantphysiology. physiological One of the main parameters, goals in recent such years as tissue has been pH, to metabolic develop newer product types and of ion agents for measuring important physiological parameters, such as tissue pH, metabolic product and concentration, hypoxia, or enzyme activity. For example, the recent discovery of a Zn2+-responsive Gd ion concentration, hypoxia, or enzyme activity. For example, the recent discovery of a Zn2+-responsive β 2+ complexGd complex has allowed has allowed monitoring monitoring of insulin of insulin secretion secretion from from pancreatic pancreatic-cells β-cells and and Zn Zn2+secretion secretionfrom prostate,from both prostate, in response both in response to glucose-induced to glucose-induced zinc secretion zinc secretion [7,11 [7,11,12].,12]. T1 agents T2 and T2 exchange CEST M M 1 p p 100 1.0 Independent r 2 ) 6 (mM contribution) (exchange 1 - High MW – of molecular s 1 - slow molecular motion 80 0.8 motion 5 Eu3+-based PARACEST 4 60 0.6 M agents Z Gd3+-based /M 3 0 T agents 40 1 Dy3+-based 0.4 T2exch agents 2 20 Low MW – Independent 0.2 fast molecular of molecular 1 -1 Inner-sphere relaxivity (mM relaxivity Inner-sphere motion motion s -1 0 0 ) 0.0 10-10 10-9 10-8 10-7 10-6 10-5 10-4 10-3 10-2 10-1 τ (water residence lifetime) M Figure 1. Schematic of T1, T2, T2-exchange, and chemical exchange saturation transfer (CEST) Figure 1. Schematic of T1, T2, T2-exchange, and chemical exchange saturation transfer (CEST) (paraCEST)(paraCEST) lanthanide lanthanide contrast contrast agents agents (CAs) (CAs) with with one one coordinated coordinated water water molecule molecule (inner-sphere (inner-spherewater, its oxygenwater, isits colored oxygen black)is colored in solutionblack) in solution (bulk and (bulk outer-sphere and outer-sphere waters waters,, oxygens oxygens are are in red).in red).Second-sphere Second- sphere water molecules (water oxygens are colored blue). The parameters that govern the relaxivity water molecules (water oxygens are colored blue). The parameters that govern the relaxivity are also are also represented: O–Ln distance (r), the mean lifetime (τM) of the water molecules in the inner represented: O–Ln distance (r), the mean lifetime (tM) of the water molecules in the inner sphere, sphere, the rotational correlation time (τR) and the electronic spin relaxation times (T1e and T2e). Below, the rotational correlation time (t ) and the electronic spin relaxation times (T and T ). Below, the the corresponding simulated plotsR are represented, showing the contrast effect (r1e1, r2, Mz/M2e 0) vs. the correspondingτM, assuming simulated standard plots parame areters represented, from the literature. showing the contrast effect (r1, r2, Mz/M0) vs. the tM, assuming standard parameters from the literature. While T1 and T2 agents comprise the majority of clinically available CAs, there are additional WhilemechanismsT1 and underT2 agents exploration comprise that may the majorityeventually of translate clinically into available clinical use. CAs, One there is T2 are-exchange additional mechanismsagents (T under2ex), which exploration is a group thatthat mayhas received eventually little translatediscussion. into The clinicalT2-exchange use. mechanism One is T2-exchange relies agentson (T intermediate2ex), which iswater a group exchange that has rates received between little bulk discussion. water and Theagent.T2 Intermediate-exchange mechanism exchange rates relies on intermediatemean that water optimum exchange T2ex agents rates lie between between bulkfaster water T1/T2-agents and agent. and slower Intermediate CEST agents exchange [13,14]. rates These mean agents shorten water T2 by a chemical exchange process rather than a relaxation process. Regulating that optimum T2ex agents lie between faster T1/T2-agents and slower CEST agents [13,14].