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16 pages, 7285 KiB

Open AccessArticle

Improved Chemical and Radiochemical Synthesis of Neuropeptide Y Y₂ Receptor Antagonist N-Methyl-JNJ-31020028 and Preclinical Positron Emission Tomography Studies

by Inês C. F. Fonseca, Mariana Lapo Pais, Fábio M. S. Rodrigues, José Sereno, Miguel Castelo-Branco, Cláudia Cavadas, Mariette M. Pereira and Antero J. Abrunhosa

Pharmaceuticals 2024, 17(4), 474; https://doi.org/10.3390/ph17040474 - 08 Apr 2024

Viewed by 519

Abstract

Neuropeptide Y (NPY) is one of the most abundant peptides in the central nervous system of mammals and is involved in several physiological processes through NPY Y₁, Y₂, Y₄ and Y₅ receptors. Of those, the Y₂ [...] Read more.

Neuropeptide Y (NPY) is one of the most abundant peptides in the central nervous system of mammals and is involved in several physiological processes through NPY Y₁, Y₂, Y₄ and Y₅ receptors. Of those, the Y₂ receptor has particular relevance for its autoreceptor role in inhibiting the release of NPY and other neurotransmitters and for its involvement in relevant mechanisms such as feeding behaviour, cognitive processes, emotion regulation, circadian rhythms and disorders such as epilepsy and cancer. PET imaging of the Y₂ receptor can provide a valuable platform to understand this receptor’s functional role and evaluate its potential as a therapeutic target. In this work, we set out to refine the chemical and radiochemical synthesis of the Y₂ receptor antagonist N-[¹¹C]Me-JNJ31020028 for in vivo PET imaging studies. The non-radioactive reference compound, N-Me-JNJ-31020028, was synthesised through batch synthesis and continuous flow methodology, with 43% and 92% yields, respectively. N-[¹¹C]Me-JNJ-31020028 was obtained with a radiochemical purity > 99%, RCY of 31% and molar activity of 156 GBq/μmol. PET imaging clearly showed the tracer’s biodistribution in several areas of the mouse brain and gut where Y₂ receptors are known to be expressed. Full article

(This article belongs to the Special Issue Next-Generation Contrast Agents for Medical Imaging)

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13 pages, 2048 KiB

Open AccessArticle

The Development of a Smart Magnetic Resonance Imaging and Chemical Exchange Saturation Transfer Contrast Agent for the Imaging of Sulfatase Activity

by Ilse M. Welleman, Friederike Reeβing, Hendrikus H. Boersma, Rudi A. J. O. Dierckx, Ben L. Feringa and Wiktor Szymanski

Pharmaceuticals 2023, 16(10), 1439; https://doi.org/10.3390/ph16101439 - 11 Oct 2023

Cited by 1 | Viewed by 1299

Abstract

The molecular imaging of biomarkers plays an increasing role in medical diagnostics. In particular, the imaging of enzyme activity is a promising approach, as it enables the use of its inherent catalytic activity for the amplification of an imaging signal. The increased activity [...] Read more.

The molecular imaging of biomarkers plays an increasing role in medical diagnostics. In particular, the imaging of enzyme activity is a promising approach, as it enables the use of its inherent catalytic activity for the amplification of an imaging signal. The increased activity of a sulfatase enzyme has been observed in several types of cancers. We describe the development and in vitro evaluation of molecular imaging agents that allow for the detection of sulfatase activity using the whole-body, non-invasive MRI and CEST imaging methods. This approach relies on a responsive ligand that features a sulfate ester moiety, which upon sulfatase-catalyzed hydrolysis undergoes an elimination process that changes the functional group, coordinating with the metal ion. When Gd³⁺ is used as the metal, the complex can be used for MRI, showing a 25% decrease at 0.23T and a 42% decrease at 4.7T in magnetic relaxivity after enzymatic conversion, thus providing a “switch-off” contrast agent. Conversely, the use of Yb³⁺ as the metal leads to a “switch-on” effect in the CEST imaging of sulfatase activity. Altogether, the results presented here provide a molecular basis and a proof-of-principle for the magnetic imaging of the activity of a key cancer biomarker. Full article

(This article belongs to the Special Issue Next-Generation Contrast Agents for Medical Imaging)

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22 pages, 2776 KiB

Open AccessArticle

A Novel Multi-Model High Spatial Resolution Method for Analysis of DCE MRI Data: Insights from Vestibular Schwannoma Responses to Antiangiogenic Therapy in Type II Neurofibromatosis

by Ka-Loh Li, Daniel Lewis, Xiaoping Zhu, David J. Coope, Ibrahim Djoukhadar, Andrew T. King, Timothy Cootes and Alan Jackson

Pharmaceuticals 2023, 16(9), 1282; https://doi.org/10.3390/ph16091282 - 11 Sep 2023

Cited by 1 | Viewed by 817

Abstract

This study aimed to develop and evaluate a new DCE-MRI processing technique that combines LEGATOS, a dual-temporal resolution DCE-MRI technique, with multi-kinetic models. This technique enables high spatial resolution interrogation of flow and permeability effects, which is currently challenging to achieve. Twelve patients [...] Read more.

This study aimed to develop and evaluate a new DCE-MRI processing technique that combines LEGATOS, a dual-temporal resolution DCE-MRI technique, with multi-kinetic models. This technique enables high spatial resolution interrogation of flow and permeability effects, which is currently challenging to achieve. Twelve patients with neurofibromatosis type II-related vestibular schwannoma (20 tumours) undergoing bevacizumab therapy were imaged at 1.5 T both before and at 90 days following treatment. Using the new technique, whole-brain, high spatial resolution images of the contrast transfer coefficient (K^trans), vascular fraction (v_p), extravascular extracellular fraction (v_e), capillary plasma flow (F_p), and the capillary permeability-surface area product (PS) could be obtained, and their predictive value was examined. Of the five microvascular parameters derived using the new method, baseline PS exhibited the strongest correlation with the baseline tumour volume (p = 0.03). Baseline v_e showed the strongest correlation with the change in tumour volume, particularly the percentage tumour volume change at 90 days after treatment (p < 0.001), and PS demonstrated a larger reduction at 90 days after treatment (p = 0.0001) when compared to K^trans or F_p alone. Both the capillary permeability-surface area product (PS) and the extravascular extracellular fraction (v_e) significantly differentiated the ‘responder’ and ‘non-responder’ tumour groups at 90 days (p < 0.05 and p < 0.001, respectively). These results highlight that this novel DCE-MRI analysis approach can be used to evaluate tumour microvascular changes during treatment and the need for future larger clinical studies investigating its role in predicting antiangiogenic therapy response. Full article

(This article belongs to the Special Issue Next-Generation Contrast Agents for Medical Imaging)

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13 pages, 2638 KiB

Open AccessArticle

Acyl Hydrazides and Acyl Hydrazones as High-Performance Chemical Exchange Saturation Transfer MRI Contrast Agents

by Shaowei Bo, Dong Zhang, Mengjie Ma, Xukai Mo, Julia Stabinska, Michael T. McMahon, Changzheng Shi and Liangping Luo

Pharmaceuticals 2023, 16(5), 639; https://doi.org/10.3390/ph16050639 - 23 Apr 2023

Cited by 2 | Viewed by 1978

Abstract

Chemical exchange saturation transfer (CEST) MRI is a versatile molecular imaging approach that holds great promise for clinical translation. A number of compounds have been identified as suitable for performing CEST MRI, including paramagnetic CEST (paraCEST) agents and diamagnetic CEST (diaCEST) agents. DiaCEST [...] Read more.

Chemical exchange saturation transfer (CEST) MRI is a versatile molecular imaging approach that holds great promise for clinical translation. A number of compounds have been identified as suitable for performing CEST MRI, including paramagnetic CEST (paraCEST) agents and diamagnetic CEST (diaCEST) agents. DiaCEST agents are very attractive because of their excellent biocompatibility and potential for biodegradation, such as glucose, glycogen, glutamate, creatine, nucleic acids, et al. However, the sensitivity of most diaCEST agents is limited because of small chemical shifts (1.0–4.0 ppm) from water. To expand the catalog of diaCEST agents with larger chemical shifts, herein, we have systematically investigated the CEST properties of acyl hydrazides with different substitutions, including aromatic and aliphatic substituents. We have tuned the labile proton chemical shifts from 2.8–5.0 ppm from water while exchange rates varied from ~680 to 2340 s⁻¹ at pH 7.2, which allows strong CEST contrast on scanners down to B₀ = 3 T. One acyl hydrazide, adipic acid dihydrazide (ADH), was tested on a mouse model of breast cancer and showed nice contrast in the tumor region. We also prepared a derivative, acyl hydrazone, which showed the furthest shifted labile proton (6.4 ppm from water) and excellent contrast properties. Overall, our study expands the catalog of diaCEST agents and their application in cancer diagnosis. Full article

(This article belongs to the Special Issue Next-Generation Contrast Agents for Medical Imaging)

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17 pages, 4181 KiB

Open AccessArticle

Manganese (II) Complex of 1,4,7-Triazacyclononane-1,4,7-Triacetic Acid (NOTA) as a Hepatobiliary MRI Contrast Agent

by Md. Kamrul Islam, Ah-Rum Baek, Byeong-Woo Yang, Soyeon Kim, Dong Wook Hwang, Sung-Wook Nam, Gang-Ho Lee and Yongmin Chang

Pharmaceuticals 2023, 16(4), 602; https://doi.org/10.3390/ph16040602 - 17 Apr 2023

Cited by 6 | Viewed by 1841

Abstract

Magnetic resonance imaging (MRI) is increasingly used to diagnose focal and diffuse liver disorders. Despite their enhanced efficacy, liver-targeted gadolinium-based contrast agents (GBCAs) raise safety concerns owing to the release of toxic Gd³⁺ ions. A π-conjugated macrocyclic chelate, Mn-NOTA-NP, was designed [...] Read more.

Magnetic resonance imaging (MRI) is increasingly used to diagnose focal and diffuse liver disorders. Despite their enhanced efficacy, liver-targeted gadolinium-based contrast agents (GBCAs) raise safety concerns owing to the release of toxic Gd³⁺ ions. A π-conjugated macrocyclic chelate, Mn-NOTA-NP, was designed and synthesized as a non-gadolinium alternative for liver-specific MRI. Mn-NOTA-NP exhibits an r₁ relaxivity of 3.57 mM⁻¹ s⁻¹ in water and 9.01 mM⁻¹ s⁻¹ in saline containing human serum albumin at 3 T, which is significantly greater than the clinically utilized Mn²⁺-based hepatobiliary drug, Mn-DPDP (1.50 mM⁻¹ s⁻¹), and comparable with that of GBCAs. Furthermore, the in vivo biodistribution and MRI enhancement patterns of Mn-NOTA-NP were similar to those of the Gd³⁺-based hepatobiliary agent, Gd-DTPA-EOB. Additionally, a 0.05 mmol/kg dose of Mn-NOTA-NP facilitated high-sensitivity tumor detection with tumor signal enhancement in a liver tumor model. Ligand-docking simulations further indicated that Mn-NOTA-NP differed from other hepatobiliary agents in their interactions with several transporter systems. Collectively, we demonstrated that Mn-NOTA-NP could be a new liver-specific MRI contrast agent. Full article

(This article belongs to the Special Issue Next-Generation Contrast Agents for Medical Imaging)

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Review

Jump to: Research

12 pages, 1007 KiB

Open AccessReview

Optimal Agents for Visualizing Collagen Tissue Microarchitecture Using Contrast-Enhanced MicroCT

by Spencer B. Glancy, Herman Douglas Morris, Vincent B. Ho and George J. Klarmann

Pharmaceuticals 2023, 16(12), 1719; https://doi.org/10.3390/ph16121719 - 12 Dec 2023

Viewed by 889

Abstract

Micro-computed tomography (microCT) is a common tool for the visualization of the internal composition of organic tissues. Collagen comprises approximately 25–35% of the whole-body protein content in mammals, and the structure and arrangement of collagen fibers contribute significantly to the integrity of tissues. [...] Read more.

Micro-computed tomography (microCT) is a common tool for the visualization of the internal composition of organic tissues. Collagen comprises approximately 25–35% of the whole-body protein content in mammals, and the structure and arrangement of collagen fibers contribute significantly to the integrity of tissues. Collagen type I is also frequently used as a key structural component in tissue-engineered and bioprinted tissues. However, the imaging of collagenous tissues is limited by their inherently low X-ray attenuation, which makes them indistinguishable from most other soft tissues. An imaging contrast agent that selectively alters X-ray attenuation is thus essential to properly visualize collagenous tissue using a standard X-ray tube microCT scanner. This review compares various contrast-enhanced techniques reported in the literature for MicroCT visualization of collagen-based tissues. An ideal microCT contrast agent would meet the following criteria: (1) it diffuses through the tissue quickly; (2) it does not deform or impair the object being imaged; and (3) it provides sufficient image contrast for reliable visualization of the orientation of individual fibers within the collagen network. The relative benefits and disadvantages of each method are discussed. Lugol’s solution (I₃K), phosphotungstic acid (H₃PW₁₂O₄₀), mercury(II) chloride (HgCl₂), and Wells–Dawson polyoxometalates came closest to fitting the criteria. While none of the contrast agents discussed in the literature met all criteria, each one has advantages to consider in the context of specific lab capabilities and imaging priorities. Full article

(This article belongs to the Special Issue Next-Generation Contrast Agents for Medical Imaging)

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29 pages, 5162 KiB

Open AccessReview

Heavy Metal-Based Nanoparticles as High-Performance X-ray Computed Tomography Contrast Agents

by Mohammad Yaseen Ahmad, Shuwen Liu, Tirusew Tegafaw, Abdullah Khamis Ali Al Saidi, Dejun Zhao, Ying Liu, Sung-Wook Nam, Yongmin Chang and Gang Ho Lee

Pharmaceuticals 2023, 16(10), 1463; https://doi.org/10.3390/ph16101463 - 15 Oct 2023

Viewed by 1229

Abstract

X-ray computed tomography (CT) contrast agents offer extremely valuable tools and techniques in diagnostics via contrast enhancements. Heavy metal-based nanoparticles (NPs) can provide high contrast in CT images due to the high density of heavy metal atoms with high X-ray attenuation coefficients that [...] Read more.

X-ray computed tomography (CT) contrast agents offer extremely valuable tools and techniques in diagnostics via contrast enhancements. Heavy metal-based nanoparticles (NPs) can provide high contrast in CT images due to the high density of heavy metal atoms with high X-ray attenuation coefficients that exceed that of iodine (I), which is currently used in hydrophilic organic CT contrast agents. Nontoxicity and colloidal stability are vital characteristics in designing heavy metal-based NPs as CT contrast agents. In addition, a small particle size is desirable for in vivo renal excretion. In vitro phantom imaging studies have been performed to obtain X-ray attenuation efficiency, which is a critical parameter for CT contrast agents, and the imaging performance of CT contrast agents has been demonstrated via in vivo experiments. In this review, we focus on the in vitro and in vivo studies of various heavy metal-based NPs in pure metallic or chemical forms, including Au, Pt, Pd, Ag, Ce, Gd, Dy, Ho, Yb, Ta, W, and Bi, and provide an outlook on their use as high-performance CT contrast agents. Full article

(This article belongs to the Special Issue Next-Generation Contrast Agents for Medical Imaging)

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27 pages, 3156 KiB

Open AccessReview

Endogenous and Exogenous Antioxidants as Agents Preventing the Negative Effects of Contrast Media (Contrast-Induced Nephropathy)

by Ina G. Panova and Alexander S. Tatikolov

Pharmaceuticals 2023, 16(8), 1077; https://doi.org/10.3390/ph16081077 - 28 Jul 2023

Viewed by 2839

Abstract

The use of conventional contrast media for diagnostic purposes (in particular, Gd-containing and iodinated agents) causes a large number of complications, the most common of which is contrast-induced nephropathy. It has been shown that after exposure to contrast agents, oxidative stress often occurs [...] Read more.

The use of conventional contrast media for diagnostic purposes (in particular, Gd-containing and iodinated agents) causes a large number of complications, the most common of which is contrast-induced nephropathy. It has been shown that after exposure to contrast agents, oxidative stress often occurs in patients, especially in people suffering from various diseases. Antioxidants in the human body can diminish the pathological consequences of the use of contrast media by suppressing oxidative stress. This review considers the research studies on the role of antioxidants in preventing the negative consequences of the use of contrast agents in diagnostics (mainly contrast-induced nephropathy) and the clinical trials of different antioxidant drugs against contrast-induced nephropathy. Composite antioxidant/contrast systems as theranostic agents are also considered. Full article

(This article belongs to the Special Issue Next-Generation Contrast Agents for Medical Imaging)

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