Synthesis and Evaluation of GdIII‐Based Magnetic Resonance Contrast Agents for Molecular Imaging of Prostate‐Specific Membrane Antigen

Magnetic resonance (MR) imaging is advantageous because it concurrently provides anatomic, functional, and molecular information. MR molecular imaging can combine the high spatial resolution of this established clinical modality with molecular profiling in vivo. However, as a result of the intrinsically low sensitivity of MR imaging, high local concentrations of biological targets are required to generate discernable MR contrast. We hypothesize that the prostate‐specific membrane antigen (PSMA), an attractive target for imaging and therapy of prostate cancer, could serve as a suitable biomarker for MR‐based molecular imaging. We have synthesized three new high‐affinity, low‐molecular‐weight Gd^III‐based PSMA‐targeted contrast agents containing one to three Gd^III chelates per molecule. We evaluated the relaxometric properties of these agents in solution, in prostate cancer cells, and in an in vivo experimental model to demonstrate the feasibility of PSMA‐based MR molecular imaging.     

New Calcium‐Selective Smart Contrast Agents for Magnetic Resonance Imaging

Calcium plays a vital role in the human body and especially in the central nervous system. Precise maintenance of Ca²⁺ levels is very crucial for normal cell physiology and health. The deregulation of calcium homeostasis can lead to neuronal cell death and brain damage. To study this functional role played by Ca²⁺ in the brain noninvasively by using magnetic resonance imaging, we have synthesized a new set of Ca²⁺‐sensitive smart contrast agents (CAs). The agents were found to be highly selective to Ca²⁺ in the presence of other competitive anions and cations in buffer and in physiological fluids. The structure of CAs comprises Gd³⁺‐DO3A (DO3A=1,4,7‐tris(carboxymethyl)‐1,4,7,10‐tetraazacyclododecane) coupled to a Ca²⁺ chelator o‐amino phenol‐N,N,O‐triacetate (APTRA). The agents are designed to sense Ca²⁺ present in extracellular fluid of the brain where its concentration is relatively high, that is, 1.2–0.8 mM . The determined dissociation constant of the CAs to Ca²⁺ falls in the range required to sense and report changes in extracellular Ca²⁺ levels followed by an increase in neural activity. In buffer, with the addition of Ca²⁺ the increase in relaxivity ranged from 100–157 %, the highest ever known for any T₁‐based Ca²⁺‐sensitive smart CA. The CAs were analyzed extensively by the measurement of luminescence lifetime measurement on Tb³⁺ analogues, nuclear magnetic relaxation dispersion (NMRD), and ¹⁷O NMR transverse relaxation and shift experiments. The results obtained confirmed that the large relaxivity enhancement observed upon Ca²⁺ addition is due to the increase of the hydration state of the complexes together with the slowing down of the molecular rotation and the retention of a significant contribution of the water molecules of the second sphere of hydration.     

Recent Progress on Manganese-Based Nanostructures as Responsive MRI Contrast Agents

Manganese-based nanostructured contrast agents (CAs) entered the field of medical diagnosis through magnetic resonance imaging (MRI) some years ago. Although some of these Mn-based CAs behave as classic T₁ contrast enhancers in the same way as clinical Gd-based molecules do, a new type of Mn nanomaterials have been developed to improve MRI sensitivity and potentially gather new functional information from tissues by using traditional T₁ contrast enhanced MRI. These nanomaterials have been designed to respond to biological environments, mainly to pH and redox potential variations. In many cases, the differences in signal generation in these responsive Mn-based nanostructures come from intrinsic changes in the magnetic properties of Mn cations depending on their oxidation state. In other cases, no changes in the nature of Mn take place, but rather the nanomaterial as a whole responds to the change in the environment through different mechanisms, including changes in integrity and hydration state. This review focusses on the chemistry and MR performance of these responsive Mn-based nanomaterials.     

Hydrogels Incorporating GdDOTA: Towards Highly Efficient Dual T(1) /T(2) MRI Contrast Agents

Do not tumble dry: Gadolinium-DOTA encapsulated into polysaccharide nanoparticles (GdDOTA?NPs) exhibited high relaxivity (r(1) =101.7?s(-1) mM(-1) per Gd(3+) ion at 37?°C and 20?MHz). This high relaxation rate is due to efficient Gd loading, reduced tumbling of the Gd complex, and the hydrogel nature of the nanoparticles. The efficacy of the nanoparticles as a T(1) /T(2) dual-mode contrast agent was studied in C6 cells.     

Approaching the Kinetic Inertness of Macrocyclic Gadolinium(III)‐Based MRI Contrast Agents with Highly Rigid Open‐Chain Derivatives

A highly rigid open‐chain octadentate ligand (H₄cddadpa) containing a diaminocylohexane unit to replace the ethylenediamine bridge of 6,6′‐[(ethane‐1,2 diylbis{(carboxymethyl)azanediyl})bis(methylene)]dipicolinic acid (H₄octapa) was synthesized. This structural modification improves the thermodynamic stability of the Gd³⁺ complex slightly (log K_GdL=20.68 vs. 20.23 for [Gd(octapa)]^?) while other MRI‐relevant parameters remain unaffected (one coordinated water molecule; relaxivity r₁=5.73 mm ^?1 s^?1 at 20 MHz and 295 K). Kinetic inertness is improved by the rigidifying effect of the diaminocylohexane unit in the ligand skeleton (half‐life of dissociation for physiological conditions is 6 orders of magnitude higher for [Gd(cddadpa)]^? (t_1/2=1.49×10⁵ h) than for [Gd(octapa)]^?. The kinetic inertness of this novel chelate is superior by 2–3 orders of magnitude compared to non‐macrocyclic MRI contrast agents approved for clinical use.     

What We Can Really Do with Bioresponsive MRI Contrast Agents

Bioresponsive MRI contrast agents hold great promise for monitoring major physiological and pathological processes in a non‐invasive manner. They are capable of altering the acquired MRI signal as a consequence of changes in their microenvironment, thus allowing real‐time functional reporting in living organisms. Importantly, chemistry offers diverse solutions for the design of agents which respond to a great number of specific targets. However, the path to the successful utilization of these biomarkers in the desired functional MRI studies involves careful consideration of multiple scientific, technical, and practical issues across various research disciplines. This Minireview highlights the critical steps for planning and executing such multidisciplinary projects with an aim to substantially improve our knowledge of essential biological processes.     

Preparation of Highly Efficient MRI Contrast Agents through Complexation of Cationic GdIII‐Containing Metallosurfactant with Biocompatible Polyelectrolytes

Novel contrast agents were developed through assembling of Gd^III‐containing metallosurfactant (MS) with biocompatible polyelectrolytes sodium hyaluronate (HA), heparinsodium (HS) and dextran sulfate sodium (DSS). The formed polyelectrolyte–surfactant complexes showed different structural patterns as the charge ratio increased, including spherical aggregates, rod‐like aggregates and network patterns in monovalent HA system, while spherical structures emerged in multivalent HS and DSS systems. Energy dispersive spectroscopy analysis and scanning electron microscopy mapping showed the presence of Gd^III in these complexes. Inductively coupled plasma atomic emission spectrometry was further used to quantify the contents of Gd^III in the assemblies. T1 magnetic resonance imaging showed that these Gd^III‐loaded complexes exhibited relaxivity of up to 63.81 mM ^?1 s^?1, much higher than that of Ominiscan (4.64 mM ^?1 s^?1). The cytotoxicity test in vitro demonstrated the excellent biocompatibility of these complexes, which is essential for clinical application.     

Yttrium‐86 Is a Positron Emitting Surrogate of Gadolinium for Noninvasive Quantification of Whole‐Body Distribution of Gadolinium‐Based Contrast Agents

Gadolinium‐based contrast agents (GBCAs) are used to provide diagnostic information in clinical magnetic resonance (MR) examinations. Gadolinium (Gd) has been detected in the brain, bone and skin of patients, months and years following GBCA administration, raising concerns about long term toxicity. Despite increased scrutiny, the concentration, chemical form and fate of the retained gadolinium species remain unknown. Importantly, the whole body biodistribution and organ clearance of GBCAs is poorly understood in humans. Gadolinium lacks suitable isotopes for nuclear imaging. We demonstrate that the yttrium‐86 isotope can be used as a gadolinium surrogate. We show that Gd and their analogous Y complexes have similar properties both in solution and in vivo, and that yttrium‐86 PET can be used to track the biodistribution of GBCAs over a two‐day period.     

Dual‐Frequency Calcium‐Responsive MRI Agents

Responsive or smart magnetic resonance imaging (MRI) contrast agents are molecular sensors that alter the MRI signal upon changes in a particular parameter in their microenvironment. Consequently, they could be exploited for visualization of various biochemical events that take place at molecular and cellular levels. In this study, a set of dual‐frequency calcium‐responsive MRI agents are reported. These are paramagnetic, fluorine‐containing complexes that produce remarkably high MRI signal changes at the ¹H and ¹⁹F frequencies at varying Ca²⁺ concentrations. The nature of the processes triggered by Ca²⁺ was revealed, allowing a better understanding of these complex systems and their further improvement. The findings indicate that these double‐frequency tracers hold great promise for development of novel functional MRI methods.     

High Relaxivity Mn2+‐Based MRI Contrast Agents

Stable Mn²⁺ mono‐ and binuclear complexes containing pentadentate 6,6′‐((methylazanediyl)bis(methylene))dipicolinic acid coordinating units give remarkably high relaxivities due to the presence of two inner‐sphere water molecules. The mononuclear derivative binds human serum albumin (HSA) with an association constant of 3372 M ^?1, which results in the replacement of the coordinated water molecules by donor atoms of protein residues. The dinuclear analogue also binds HSA while leaving one of the Mn²⁺ centres exposed to the solvent with two coordinated water molecules. Thus, this complex shows remarkably high relaxivities upon protein binding (39.0 mM ^?1 s^?1 per Mn, at 20 MHz and 37 °C).     

Cleaved Iron Oxide Nanoparticles as T2 Contrast Agents for Magnetic Resonance Imaging

Iron oxide nanoparticles as contrast agents are reported to effectively improve magnetic resonance imaging of tissues and cells. In this work, cleaved iron oxide nanoparticles (CIONPs) were generated from hydrophobic FeO nanoparticles (HIONPs) by coating their surfaces with PEG‐phospholipids, oxidizing them under water, and slowly removing the residual FeO phase in phthalate buffer. The synthesized CIONPs showed good r₂ values of up to 258 s^?1 mM ^?1. Thus, the CIONPs can be employed as vectors for drug delivery due to their unique structure with an empty inner space, which enables their use in a wide range of applications.     

MRI Contrast Agents in Glycobiology

Molecular recognition involving glycoprotein-mediated interactions is ubiquitous in both normal and pathological natural processes. Therefore, visualization of these interactions and the extent of expression of the sugars is a challenge in medical diagnosis, monitoring of therapy, and drug design. Here, we review the literature on the development and validation of probes for magnetic resonance imaging using carbohydrates either as targeting vectors or as a target. Lectins are important targeting vectors for carbohydrate end groups, whereas selectins, the asialoglycoprotein receptor, sialic acid end groups, hyaluronic acid, and glycated serum and hemoglobin are interesting carbohydrate targets.     

肿瘤诊断的MRI造影剂*

磁共振成像是临床上常用的无侵入性肿瘤早期诊断手段,常常需要借助造影剂来提高诊断能力。造影剂可缩短质子的弛豫时间,间接地改变质子所产生的信号强度并能改变体内局部组织中水质子的弛豫速率,提高正常与患病部位的成像对比度。本文较系统地评述了目前国内外用于肿瘤成像造影剂的研究进展,并讨论了顺磁性造影剂的发展前景。     

Tuning Glutamine Binding Modes in Gd‐DOTA‐Based Probes for an Improved MRI Visualization of Tumor Cells

Three new magnetic resonance imaging probes that target glutamine transporters have been synthesized. They consist of a Gd‐DOTA‐monoamide moiety (DOTA=1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid) linked through a six carbon atom chain to a vector represented by a glutamine residue bound through α‐carboxylic, γ‐carboxamidic, or α‐amino functionalities. Their uptake by HTC (rat hepatocarcinoma) and healthy rat hepatocytes has shown that the system containing the glutamine vector bound through the α‐carboxylic group displays a markedly higher affinity for tumor cells. The observed behavior is rationalized in terms of the exploitation of an additional glutamine transporter active in hepatic tumor cells.