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.     

Synthesis of （p—Substituted phenyl）azo Calix[4] arenes

A novel method for the preparation of chromogenic calixarenes with azo groups was reported.p-Substituted(-NO2,-CH3,-Cl)amilines were diazotized with isoamyl nitrite in EtONa/EtOH under refluxing condition.Fifteen mono-,bis-,tris-and tetrakis(p-substituted phenyl)azo calix[4]arenes (including proximal and distal isomers) were obtainged respectively by diazo-coupling in different molar ratio to calix[4]arenes(1) under pH=7.5-9.0 in non-aqueous solution at 0-5℃.^1H NMR and ^13C NMR spectra of (p-substtituted phenyl)azo calix[4]-arenes indicated that they existed in cone conformation in solution.     

Serum Albumin Targeted,pH‐Dependent Magnetic Resonance Relaxation Agents

The objective of this work was the synthesis of serum albumin targeted, Gd^III‐based magnetic resonance imaging (MRI) contrast agents exhibiting a strong pH‐dependent relaxivity. Two new complexes ( Gd‐glu and Gd‐bbu ) were synthesized based on the DO3A macrocycle modified with three carboxyalkyl substituents α to the three ring nitrogen atoms, and a biphenylsulfonamide arm. The sulfonamide nitrogen coordinates the Gd in a pH‐dependent fashion, resulting in a decrease in the hydration state, q, as pH is increased and a resultant decrease in relaxivity (r₁). In the absence of human serum albumin (HSA), r₁ increases from 2.0 to 6.0 mM ^?1 s^?1 for Gd‐glu and from 2.4 to 9.0 mM ^?1 s^?1 for Gd‐bbu from pH 5 to 8.5 at 37 °C, 0.47 T, respectively. These complexes (0.2 mM ) are bound (>98.9 %) to HSA (0.69 mM ) over the pH range 5–8.5. Binding to albumin increases the rotational correlation time and results in higher relaxivity. The r₁ increased 120 % (pH 5) and 550 % (pH 8.5) for Gd‐glu and 42 % (pH 5) and 260 % (pH 8.5) for Gd‐bbu . The increases in r₁ at pH 5 were unexpectedly low for a putative slow tumbling q=2 complex. The Gd‐bbu system was investigated further. At pH 5, it binds in a stepwise fashion to HSA with dissociation constants K_d1=0.65, K_d2=18, K_d3=1360 μM . The relaxivity at each binding site was constant. Luminescence lifetime titration experiments with the Eu^III analogue revealed that the inner‐sphere water ligands are displaced when the complex binds to HSA resulting in lower than expected r₁ at pH 5. Variable pH and temperature nuclear magnetic relaxation dispersion (NMRD) studies showed that the increased r₁ of the albumin‐bound q=0 complexes is due to the presence of a nearby water molecule with a long residency time (1–2 ns). The distance between this water molecule and the Gd ion changes with pH resulting in albumin‐bound pH‐dependent relaxivity.     

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.     

磁共振成像造影剂的一些进展

本文综述了近年来磁共振成像造影剂的一些研究进展,对70余种钆配合物作了分类讨论。     

Synthesis of Ionizable Calix[4]arenes for Chelation of Selected Divalent Cations

Two sets of functionalised calix[4]arenes, either with a 1,3-crown ether bridge or with an open-chain oligo ether moiety in 1,3-position were prepared and further equipped with additional deprotonisable sulfonamide groups to establish chelating systems for selected cations Sr²⁺, Ba²⁺, and Pb²⁺ ions. To improve the complexation behaviour towards these cations, calix[4]arenes with oligo ether groups and modified crowns of different sizes were synthesized. Association constants were determined by UV/Vis titration in acetonitrile using the respective perchlorate salts and logK values between 3.2 and 8.0 were obtained. These findings were supported by the calculation of the binding energies exemplarily for selected complexes with Ba²⁺.     

Dysprosium Complexes and Their Micelles as Potential Bimodal Agents for Magnetic Resonance and Optical Imaging

Six diethylene triamine pentaacetic acid (DTPA) bisamide derivatives functionalized with p‐toluidine (DTPA‐BTolA), 6‐aminocoumarin (DTPA‐BCoumA), 1‐naphthalene methylamine (DTPA‐BNaphA), 4‐ethynylaniline (DTPA‐BEthA), p‐dodecylaniline (DTPA‐BC₁₂PheA) and p‐tetradecyl‐aniline (DTPA‐BC₁₄PheA) were coordinated to dysprosium(III) and the magnetic and optical properties of the complexes were examined in detail. The complexes consisting of amphiphilic ligands (DTPA‐BC₁₂PheA and DTPA‐BC₁₄PheA) were further assembled into mixed micelles. Upon excitation into the ligand levels, the complexes display characteristic Dy^III emission with quantum yields of 0.3–0.5 % despite the presence of one water molecule in the first coordination sphere. A deeper insight into the energy‐transfer processes has been obtained by studying the photophysical properties of the corresponding Gd^III complexes. Since the luminescence quenching effect is decreased by the intervention of non‐ionic surfactant, quantum yields up to 1 % are obtained for the micelles. The transverse relaxivity r₂ per Dy^III ion at 500 MHz and 310 K reaches a maximum value of 27.4 s^?1 mM ^?1 for Dy‐DTPA‐BEthA and 36.0 s^?1 mM ^?1 for the Dy‐DTPA‐BC₁₂PheA assemblies compared with a value of 0.8 s^?1 mM ^?1 for Dy‐DTPA. The efficient T₂ relaxation, especially at high magnetic field strengths, is sustained by the high magnetic moment of the dysprosium ion, the coordination of water molecules with slow water exchange kinetics and long rotational correlation times. These findings open the way to the further development of bimodal optical and magnetic resonance imaging probes starting from single lanthanide compounds.     

磁共振成像造影剂的研究进展

磁共振成像技术已成为临床医学影像学检查的重要手段,30%以上的磁共振成像诊断需要使用造影剂,因此磁共振成像造影剂也成为一种重要的临床诊断药物.本文简单介绍磁共振成像造影剂的定义、原理和分类,并对当前的研究进展进行了的评述,认为开发具有靶向性、高弛豫效率、使用安全的造影剂是研究的主要方向.     

Calix[4]arenes with 1,2- and 1,3-upper rim tetrathiafulvalene bridges

Herein we report the synthesis of several calix[4]arene derivatives with tetrathiafulvalene bridges at the upper rim. Calix[4]arene-tetrathiafulvalene (TTF) conjugates 4a–d, fixed in cone conformation and comprising two smaller 1,2-bridges, were prepared by cyclisation of tetrakis-chloromethylated calix[4]arene 1 with 2,3-dithiolates of TTFs. Larger calix[4]arene-TTF macrocycles 14 and 15, also in cone conformation, contain 1,3-bridges and were synthesised by cyclisation of 2,6- and 2,7-dithiolates of TTFs with bis-bromomethylated calix[4]arene 7. Redox properties of new calix[4]arene-TTF conjugates were characterised using cyclic voltammetry.     

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.     

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).     

硅胶键合杯[4]芳烃固定相的合成和核磁共振表征

杯芳烃（Ｃａｌｉｘａｒｅｎｅｓ）［１］是由苯酚单体通过亚甲基单元连接起来的一类性质稳定的环状低聚物．由于它的独特结构特点以及由此表现出来的特有性能,使之已成为继冠醚和环糊精之后的第三代超分子［２］．近年来,杯芳烃在色谱中的应用已经引起人们的关注,有关...     

Long synthetic nanotubes from calix[4]arenes

We report the synthesis and encapsulation properties of long (up to 5 nm) molecular nanotubes 1-4, which are based on calix[4]arenes and can be filled with multiple nitrosonium (NO(+)) ions upon reaction with NO(2)/N(2)O(4) gases. These are among the largest nanoscale molecular containers prepared to date and can entrap up to five guests. The structure and properties of tubular complexes 1(NO(+))(2)-4(NO(+))(5) were studied by UV/Vis, FTIR, and (1)H NMR spectroscopy in solution, and also by molecular modeling. Entrapment of NO(+) in 1(NO(+))(2)-4(NO(+))(5) is reversible, and addition of [18]crown-6 quickly recovers starting tubes 1-4. The FTIR and titration data revealed enhanced binding of NO(+) in longer tubes, which may be due to cooperativity. The described nanotubes may serve as materials for storing and converting NO(x) and also offer a promise to further develop supramolecular chemistry of molecular containers. These findings also open wider perspectives towards applications of synthetic nanotubes as alternatives to carbon nanotubes.     

Synthesis of Core-Shell Magnetic Supramolecular Nanocatalysts based on Amino-Functionalized Calix[4]arenes for the Synthesis of 4H-Chromenes by Ultrasonic Waves

One of the most common phenol-formaldehyde cyclic oligomers from hydroxyalkylation reactions that exhibit supramolecular chemistry are calixarenes. These macrocyclic compounds are qualified to act as synthetic catalysts due to their specific features including being able to form host-guest complexes, having unique structural scaffolds and their relative ease of chemical modifications with a variety of functions on their upper rim and lower rim. Here, a functional magnetic nanocatalyst was designed and synthesized by using a synthetic amino-functionalized calix[4]arene. Its catalytic activity was evaluated in a one-pot synthesis of 2-amino-4H-chromene derivatives. Besides, this novel magnetic nanocatalyst was characterized by spectroscopic and analytical techniques such as FT-IR, EDX, FE-SEM, TEM VSM, XRD analysis.     

Dimeric Capsules Formed by Tetra‐CMPO Derivatives of (Thia)Calix[4]arenes

Thiacalix[4]arene 2 , calix[4]arene 3 a and its tetraether fixed in the cone conformation 3 b form homo‐ and heterodimeric capsules in apolar solvents, which are held together by a seam of NH???O=P hydrogen bonds between carbamoylmethyl phospine oxide functions attached to their wide rim. Their internal volume of ～370 ų requires the inclusion of a suitable guest. Although neutral molecules such as adamantane (derivatives) or tetraethylammonium cations form kinetically stable complexes (¹H‐ and ³¹P‐time scale), the included solvent is rapidly exchanged. The internal mobility of the included tetraethylammonium cation is distinctly higher (ΔG=42.5 and 49.7 kJ mol^?1 for 3 a and 3 b ) than that for similar capsules of tetraurea calix[4]arenes 1 . Mixtures of 1 with 2 , 3 a , or 3 b contain only the two homodimers but the heterodimerization occurs with the tetraloop tetraurea 6 , which cannot form homodimers. Two dimers with cationic guests ( 2? (C₅H₅)₂Co⁺ ?2 and 3 a? Et₃NH⁺ ? H₂O ?3 a ) were confirmed by single‐crystal X‐ray analysis.     

Spatially Resolved Quantification of Gadolinium(III)‐Based Magnetic Resonance Agents in Tissue by MALDI Imaging Mass Spectrometry after In Vivo MRI

Gadolinium(III)‐based contrast agents improve the sensitivity and specificity of magnetic resonance imaging (MRI), especially when targeted contrast agents are applied. Because of nonlinear correlation between the contrast agent concentration in tissue and the MRI signal obtained in vivo, quantification of certain biological or pathophysiological processes by MRI remains a challenge. Up to now, no technology has been able to provide a spatially resolved quantification of MRI agents directly within the tissue, which would allow a more precise verification of in vivo imaging results. MALDI imaging mass spectrometry for spatially resolved in situ quantification of gadolinium(III) agents, in correlation to in vivo MRI, were evaluated. Enhanced kinetics of Gadofluorine M were determined dynamically over time in a mouse model of myocardial infarction. MALDI imaging was able to corroborate the in vivo imaging MRI signals and enabled in situ quantification of the gadolinium probe with high spatial resolution.