Gd Complexes of DO3A-(Biphenyl-2,2′-bisamides) Conjugates as MRI Blood-Pool Contrast Agents

We report the synthesis of DO3A derivatives of 2,2′-diaminobiphenyl (<b>1a</b>,<b>b</b>) and their Gd complexes of the type [Gd­(<b>1</b>)­(H₂O)]·<i>x</i>H₂O (<b>2a</b>,<b>b</b>) for use as new MRI blood-pool contrast agents (BPCAs) that provide strong and prolonged vascular enhancement. Pharmacokinetic inertness of <b>2</b> compares well with that of structurally related Dotarem, a DOTA-based MRI CA currently in use. The <i>R</i>₁ relaxivity in water reaches 7.3 mM^–1 s^–1, which is approximately twice as high as that of Dotarem (<i>R</i>₁ = 3.9 mM^–1 s^–1). They show interaction with HSA to give association constants (<i>K</i>_a) in the order of two (∼10²), revealing the existence of the blood-pool effect. The in vivo MR images of mice obtained with <b>2</b> are coherent, showing strong signal enhancement in both heart, abdominal aorta, and small vessels. Furthermore, the brain tumor is vividly enhanced for an extended period of time

Surface Design of Eu-Doped Iron Oxide Nanoparticles for Tuning the Magnetic Relaxivity

Relaxivity tuning of nanomaterials with the intrinsic <i>T</i>₁–<i>T</i>₂ dual-contrast ability has great potential for MRI applications. Until now, the relaxivity tuning of T₁ and T₂ dual-modal MRI nanoprobes has been accomplished through the dopant, size, and morphology of the nanoprobes, leaving room for bioapplications. However, a surface engineering method for the relaxivity tuning was seldom reported. Here, we report the novel relaxivity tuning method based on the surface engineering of dual-mode <i>T</i>₁–<i>T</i>₂ MRI nanoprobes (DMNPs), along with protein interaction monitoring with the DMNPs as a potential biosensor application. Core nanoparticles (NPs) of europium-doped iron oxide (EuIO) are prepared by a thermal decomposition method. As surface materials, citrate (Cit), alendronate (Ale), and poly­(maleic anhydride-<i>alt</i>-1-octadecene)/poly­(ethylene glycol) (PP) are employed for the relaxivity tuning of the NPs based on surface engineering, resulting in EuIO-Cit, EuIO-Ale, and EuIO-PP, respectively. The key achievement of the current study is that the surface materials of the DMNP have significant impacts on the <i>r</i>₁ and <i>r</i>₂ relaxivities. The correlation between the hydrophobicity of the surface material and longitudinal relaxivity (<i>r</i>₁) of EuIO NPs presents an exponential decay feature. The <i>r</i>₁ relaxivity of EuIO-Cit is 13.2-fold higher than that of EuIO-PP. EuIO can act as <i>T</i>₁–<i>T</i>₂ dual-modal (EuIO-Cit) or <i>T</i>₂-dominated MRI contrast agents (EuIO-PP) depending on the surface engineering. The feasibility of using the resulting nanosystem as a sensor for environmental changes, such as albumin interaction, was also explored. The albumin interaction on the DMNP shows both <i>T</i>₁ and <i>T</i>₂ relaxation time changes as mutually confirmative information. The relaxivity tuning approach based on the surface engineering may provide an insightful strategy for bioapplications of DMNPs and give a fresh impetus for the development of novel stimuli-responsive MRI nanoplatforms with <i>T</i>₁ and <i>T</i>₂ dual-modality for various biomedical applications

Heteronuclear Gd-^99mTc Complex of DTPA-Bis(histidylamide) Conjugate as a Bimodal MR/SPECT Imaging Probe

The work describes the synthesis and in vivo application of heterotrimetallic complexes of the type {Gd­(H₂O)­[(M­(H₂O)­(CO)₃)₂(<b>1</b>)]} {<b>1</b> = DTPA-bis­(histidyl-amide); <i>M</i> = Re (<b>3a</b>); ^99mTc (<b>3b</b>)} for dual modality MR/SPECT imaging. Here, the DTPA-bis­(histidylamide) conjugate functions as a trinucleating chelate incorporating Gd in the DTPA core with Re or ^99mTc in the pair of histidylamide side arms. The two complexes are chemically equivalent as revealed by HPLC, and their “cocktail mixture” (<b>3a</b> + <b>3b</b>) has demonstrated itself to be essentially a single bimodal imaging probe. The present system has thus overcome the sensitivity difference problem between MRI and SPECT and paved the way for practical applications

Manganese Complex of Ethylene­diamine­tetraacetic Acid (EDTA)–Benzothiazole Aniline (BTA) Conjugate as a Potential Liver-Targeting MRI Contrast Agent

A novel manganese­(II) complex based on an ethylene­diamine­tetraacetic acid (EDTA) coordination cage bearing a benzothiazole aniline (BTA) moiety (Mn-EDTA-BTA) was designed and synthesized for use as a liver-specific MRI contrast agent with high chelation stability. In addition to forming a hydrophilic, stable complex with Mn²⁺, this new Mn chelate was rapidly taken up by liver hepatocytes and excreted by the kidneys and biliary system. The kinetic inertness and <i>R</i>₁ relaxivity of the complex were much higher than those of mangafodipir trisodium (MnDPDP), a clinically approved liver-specific MRI contrast agent. The diagnostic utility of this new Mn complex in MRI was demonstrated by high-sensitivity tumor detection in an animal model of liver cancer

Gadolinium Complex of ¹²⁵I/¹²⁷I‑RGD-DOTA Conjugate as a Tumor-Targeting SPECT/MR Bimodal Imaging Probe

The work describes the synthesis and in vivo application of [Gd­(L)­(H₂O)]·<i>x</i>H₂O, where L is a (¹²⁵I/¹²⁷I-RGD)- DOTA conjugate, as a tumor-targeting SPECT/MR bimodal imaging probe. Here, (¹²⁵I/¹²⁷I-RGD)-DOTA signifies a “cocktail mixture” of radioisotopic (<b>1a</b>, L = ¹²⁵I-RGD-DOTA) and natural (<b>1b</b>, L = ¹²⁷I-RGD-DOTA) Gd complexes. The two complexes are chemically equivalent as revealed by HPLC, and their cocktail mixture exhibits the integrin-specific tumor enhancement, demonstrating that they constitute essentially a single bimodal imaging probe. Employment of a cocktail mixture thus proves to be a sole and practical approach to overcome the sensitivity difference problem between MRI and SPECT

Gadolinium Complex of 1,4,7,10-Tetraazacyclo­dodecane-1,4,7-trisacetic Acid (DO3A)–Ethoxybenzyl (EOB) Conjugate as a New Macrocyclic Hepatobiliary MRI Contrast Agent

We report the synthesis of a macrocyclic Gd chelate based on a 1,4,7,10-tetraazacyclo­dodecane-1,4,7-trisacetic acid (DO3A) coordinationn cage bearing an ethoxybenzyl (EOB) moiety and discuss its use as a <i>T</i>₁ hepatobiliary magnetic resonance imaging (MRI) contrast agent. The new macrocyclic liver agent shows high chelation stability and high <i>r</i>₁ relaxivity compared with linear-type Gd chelates, which are the current clinically approved liver agents. Our macrocyclic, liver-specific Gd chelate was evaluated in vivo through biodistribution analysis and liver MRI, which demonstrated its high tumor detection sensitivity and suggested that the new Gd complex is a promising contrast agent for liver cancer imaging

Vivid Tumor Imaging Utilizing Liposome-Carried Bimodal Radiotracer

By developing a new bimodal radioactive tracer that emits both luminescence and nuclear signals, a trimodal liposome for optical, nuclear, and magnetic resonance imaging is efficiently prepared. Fast clearance of the radiotracer from reticuloendothelial systems enables vivid tumor imaging with minimum background

Radiometallic Complexes of DO3A-Benzothiazole Aniline for Nuclear Medicine Theranostics

To develop a radioactive metal complex platform for tumor theranostics, we introduced three radiopharmaceutical derivatives of 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid-benzothiazole aniline (DO3A-BTA, L1) labeled with medical radioisotopes for diagnosis (⁶⁸Ga/⁶⁴Cu) and therapy (¹⁷⁷Lu). The tumor-targeting ability of these complexes was demonstrated in a cellular uptake experiment, in which ¹⁷⁷Lu-L1 exhibited markedly higher uptake in HeLa cells than the ¹⁷⁷Lu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid complex. According to in vivo positron emission tomography imaging, high accumulation of ⁶⁸Ga-L1 and ⁶⁴Cu-L1 was clearly visualized in the tumor site, while ¹⁷⁷Lu-L1 showed therapeutic efficacy in therapy experiments. Consequently, this molecular platform represents a useful approach in nuclear medicine toward tumor-theranostic radiopharmaceuticals when ⁶⁸Ga-L1 or ⁶⁴Cu-L1 is used for diagnosis, ¹⁷⁷Lu-L1 is used for therapy, or two of the compounds are used in conjunction with each other

High in Vivo Stability of ⁶⁴Cu-Labeled Cross-Bridged Chelators Is a Crucial Factor in Improved Tumor Imaging of RGD Peptide Conjugates

Although the importance of bifunctional chelators (BFCs) is well recognized, the chemophysical parameters of chelators that govern the biological behavior of the corresponding bioconjugates have not been clearly elucidated. Here, five BFCs closely related in structure were conjugated with a cyclic RGD peptide and radiolabeled with Cu-64 ions. Various biophysical and chemical properties of the Cu­(II) complexes were analyzed with the aim of identifying correlations between individual factors and the biological behavior of the conjugates. Tumor uptake and body clearance of the ⁶⁴Cu-labeled bioconjugates were directly compared by animal PET imaging in animal models, which was further supported by biodistribution studies. Conjugates containing propylene cross-bridged chelators showed higher tumor uptake, while a closely related ethylene cross-bridged analogue exhibited rapid body clearance. High in vivo stability of the copper–chelator complex was strongly correlated with high tumor uptake, while the overall lipophilicity of the bioconjugate affected both tumor uptake and body clearance

Demographic and clinical information for fibromyalgia and control groups.

<p>FIQ, Fibromyalgia impact questionnaire; BFI, Brief fatigue inventory; BDI, Beck depression inventory; BAI, Beck anxiety inventory; IQ, Intelligence quotient.</p