In Vivo Nuclear Molecular Imaging in Drug Development and Pharmacological Research

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Radiopharmaceutical Sciences".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 35073

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Special Issue Editor

Nemours Children's Hospital, Delaware, DE 19803, USA
Interests: radiochemistry; nuclear medicine; medicinal chemistry; organic synthesis; molecular imaging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Molecular imaging can provide real-time noninvasive visualization, characterization, and quantification of biological processes at the molecular levels in intact living subjects. Nuclear molecular imaging has been receiving significant attention due to its high sensitivity and noninvasive imaging profile. The unique imaging modality enables scientists to study in vivo functional information that is usually challenging or impossible by other imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT). Furthermore, radioisotope-labeled imaging agents can detect the onset of abnormalities before any morphological changes. With the emerging use of precision medicine and personalized treatment in patient management, nuclear molecular imaging is at the forefront of the trend in aiding diagnosis, monitoring disease progression, and evaluating therapeutic responses.

This Special Issue of Pharmaceuticals invites both original and review articles related to in vivo nuclear imaging in drug development and pharmacological research, and we welcome submissions of the following topics: (1) identify and validate in vivo biomarkers by nuclear molecular imaging; (2) evaluation of on-target and off-target effects, receptor occupancy, and biodistribution information of the radiotracers; (3) in vivo biorthogonal reaction involved radioisotopes to probe mechanism of diseases; (4) determine the pharmacokinetic, pharmacodynamic, and metabolic profiles; (5) dosimetry studies, kinetic modeling of radiotracers in pre-clinical research and clinical investigation; (6) bench-to-bedside clinical translation of radiotracers.

Dr. Xuyi Yue
Guest Editor

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Keywords

  • nuclear molecular imaging
  • drug development
  • in vivo application
  • biomarker
  • nuclear precision medicine

Published Papers (13 papers)

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Editorial

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5 pages, 212 KiB  
Editorial
Special Issue “In Vivo Nuclear Molecular Imaging in Drug Development and Pharmacological Research”
by Xuyi Yue
Pharmaceuticals 2023, 16(3), 459; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16030459 - 20 Mar 2023
Viewed by 1009
Abstract
Nuclear molecular imaging is increasingly important in aiding diagnosis, monitoring disease progression, and assessing response to treatment [...] Full article

Research

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13 pages, 1946 KiB  
Article
Development and Validation of [3H]OF-NB1 for Preclinical Assessment of GluN1/2B Candidate Drugs
by Hazem Ahmed, Livio Gisler, Nehal H. Elghazawy, Claudia Keller, Wolfgang Sippl, Steven H. Liang, Ahmed Haider and Simon M. Ametamey
Pharmaceuticals 2022, 15(8), 960; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15080960 - 02 Aug 2022
Cited by 4 | Viewed by 1556
Abstract
GluN2B-enriched N-methyl-D-aspartate receptors (NMDARs) are implicated in several neurodegenerative and psychiatric diseases, such as Alzheimer’s disease. No clinically valid GluN1/2B therapeutic exists due to a lack of selective GluN2B imaging tools, and the state-of-the-art [3H]ifenprodil shows poor selectivity [...] Read more.
GluN2B-enriched N-methyl-D-aspartate receptors (NMDARs) are implicated in several neurodegenerative and psychiatric diseases, such as Alzheimer’s disease. No clinically valid GluN1/2B therapeutic exists due to a lack of selective GluN2B imaging tools, and the state-of-the-art [3H]ifenprodil shows poor selectivity in drug screening. To this end, we developed a tritium-labeled form of OF-NB1, a recently reported selective GluN1/2B positron emission tomography imaging (PET) agent, with a molar activity of 1.79 GBq/µmol. The performance of [3H]OF-NB1 and [3H]ifenprodil was compared through head-to-head competitive binding experiments, using the GluN1/2B ligand CP-101,606 and the sigma-1 receptor (σ1R) ligand SA-4503. Contrary to [3H]ifenprodil, the usage of [3H]OF-NB1 differentiated between GluN1/2B and σ1R binding components. These results were corroborated by observations from PET imaging experiments in Wistar rats using the σ1R radioligand [18F]fluspidine. To unravel the binding modes of OF-NB1 and ifenprodil in GluN1/2B and σ1Rs, we performed a retrospective in silico study using a molecular operating environment. OF-NB1 maintained similar interactions to GluN1/2B as ifenprodil, but only ifenprodil successfully fitted in the σ1R pocket, thereby explaining the high GluN1/2B selectivity of OF-NB1 compared to ifenprodil. We successfully showed in a proof-of-concept study the superiority of [3H]OF-NB1 over the gold standard [3H]ifenprodil in the screening of potential GluN1/2B drug candidates. Full article
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17 pages, 3813 KiB  
Article
[99mTc]Tc-iFAP/SPECT Tumor Stroma Imaging: Acquisition and Analysis of Clinical Images in Six Different Cancer Entities
by Paola Vallejo-Armenta, Guillermina Ferro-Flores, Clara Santos-Cuevas, Francisco Osvaldo García-Pérez, Pamela Casanova-Triviño, Bayron Sandoval-Bonilla, Blanca Ocampo-García, Erika Azorín-Vega and Myrna Luna-Gutiérrez
Pharmaceuticals 2022, 15(6), 729; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15060729 - 09 Jun 2022
Cited by 7 | Viewed by 2891
Abstract
Fibroblast activation protein (FAP) is highly expressed on the cancer-associated fibroblasts (CAF) of the tumor stroma. Recently, we reported the preclinical evaluation and clinical biokinetics of a novel 99mTc-labeled FAP inhibitor radioligand ([99mTc]Tc-iFAP). This research aimed to evaluate [99m [...] Read more.
Fibroblast activation protein (FAP) is highly expressed on the cancer-associated fibroblasts (CAF) of the tumor stroma. Recently, we reported the preclinical evaluation and clinical biokinetics of a novel 99mTc-labeled FAP inhibitor radioligand ([99mTc]Tc-iFAP). This research aimed to evaluate [99mTc]Tc-iFAP for the tumor stroma imaging of six different cancerous entities and analyze them from the perspective of stromal heterogeneity. [99mTc]Tc-iFAP was prepared from freeze-dried kits with a radiochemical purity of 98 ± 1%. The study included thirty-two patients diagnosed with glioma (n = 5); adrenal cortex neuroendocrine tumor (n = 1); and breast (n = 21), lung (n = 2), colorectal (n = 1) and cervical (n = 3) cancer. Patients with glioma had been evaluated with a previous cranial MRI scan and the rest of the patients had been involved in a [18F]FDG PET/CT study. All oncological diagnoses were corroborated histopathologically. The patients underwent SPECT/CT brain imaging (glioma) or thoracoabdominal imaging 1 h after [99mTc]Tc-iFAP administration (i.v., 735 ± 63 MBq). The total lesions (n = 111) were divided into three categories: primary tumors (PT), lymph node metastases (LNm), and distant metastases (Dm). [99mTc]Tc-iFAP brain imaging was positive in four high-grade WHO III–IV gliomas and negative in one treatment-naive low-grade glioma. Both [99mTc]Tc-iFAP and [18F]FDG detected 26 (100%) PT, although the number of positive LNm and Dm was significantly higher with [18F]FDG [82 (96%)], in comparison to [99mTc]Tc-iFAP imaging (35 (41%)). Peritoneal carcinomatosis lesions in a patient with recurrent colorectal cancer were only visualized with [99mTc]Tc-iFAP. In patients with breast cancer, a significant positive correlation was demonstrated among [99mTc]Tc-iFAP uptake values (Bq/cm3) of PT and the molecular subtype, being higher for subtypes HER2+ and Luminal B HER2-enriched. Four different CAF subpopulations have previously been described for LNm of breast cancer (from CAF-S1 to CAF-S4). The only subpopulation that expresses FAP is CAF-S1, which is preferentially detected in aggressive subtypes (HER2 and triple-negative), confirming that FAP+ is a marker for poor disease prognosis. The results of this pilot clinical research show that [99mTc]Tc-iFAP SPECT imaging is a promising tool in the prognostic assessment of some solid tumors, particularly breast cancer. Full article
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13 pages, 1769 KiB  
Article
Production of GMP-Compliant Clinical Amounts of Copper-61 Radiopharmaceuticals from Liquid Targets
by Alexandra I. Fonseca, Vítor H. Alves, Sérgio J. C. do Carmo, Magda Silva, Ivanna Hrynchak, Francisco Alves, Amílcar Falcão and Antero J. Abrunhosa
Pharmaceuticals 2022, 15(6), 723; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15060723 - 07 Jun 2022
Cited by 8 | Viewed by 2215
Abstract
PET imaging has gained significant momentum in the last few years, especially in the area of oncology, with an increasing focus on metal radioisotopes owing to their versatile chemistry and favourable physical properties. Copper-61 (t1/2 = 3.33 h, 61% β+, [...] Read more.
PET imaging has gained significant momentum in the last few years, especially in the area of oncology, with an increasing focus on metal radioisotopes owing to their versatile chemistry and favourable physical properties. Copper-61 (t1/2 = 3.33 h, 61% β+, Emax = 1.216 MeV) provides unique advantages versus the current clinical standard (i.e., gallium-68) even though, until now, no clinical amounts of 61Cu-based radiopharmaceuticals, other than thiosemicarbazone-based molecules, have been produced. This study aimed to establish a routine production, using a standard medical cyclotron, for a series of widely used somatostatin analogues, currently labelled with gallium-68, that could benefit from the improved characteristics of copper-61. We describe two possible routes to produce the radiopharmaceutical precursor, either from natural zinc or enriched zinc-64 liquid targets and further synthesis of [61Cu]Cu-DOTA-NOC, [61Cu]Cu-DOTA-TOC and [61Cu]Cu-DOTA-TATE with a fully automated GMP-compliant process. The production from enriched targets leads to twice the amount of activity (3.28 ± 0.41 GBq vs. 1.84 ± 0.24 GBq at EOB) and higher radionuclidic purity (99.97% vs. 98.49% at EOB). Our results demonstrate, for the first time, that clinical doses of 61Cu-based radiopharmaceuticals can easily be obtained in centres with a typical biomedical cyclotron optimised to produce 18F-based radiopharmaceuticals. Full article
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20 pages, 3384 KiB  
Article
Fluorine-18 Labeled Urea-Based Ligands Targeting Prostate-Specific Membrane Antigen (PSMA) with Increased Tumor and Decreased Renal Uptake
by Falguni Basuli, Tim E. Phelps, Xiang Zhang, Carolyn C. Woodroofe, Jyoti Roy, Peter L. Choyke, Rolf E. Swenson and Elaine M. Jagoda
Pharmaceuticals 2022, 15(5), 597; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050597 - 13 May 2022
Cited by 2 | Viewed by 1784
Abstract
High expression of prostate-specific membrane antigen (PSMA) in prostate cancers prompted the development of the PSMA-targeted PET-imaging agent [18F]DCFPyL, which was recently approved by the FDA. Fluorine-18-labeled Lys–Urea–Glu-based oxime derivatives of [18F]DCFPyL were prepared for the comparison of their [...] Read more.
High expression of prostate-specific membrane antigen (PSMA) in prostate cancers prompted the development of the PSMA-targeted PET-imaging agent [18F]DCFPyL, which was recently approved by the FDA. Fluorine-18-labeled Lys–Urea–Glu-based oxime derivatives of [18F]DCFPyL were prepared for the comparison of their in vitro and in vivo properties to potentially improve kidney clearance and tumor targeting. The oxime radiotracers were produced by condensation of an aminooxy functionalized PSMA-inhibitor Lys–Urea–Glu scaffold with fluorine-18-labeled aldehydes. The radiochemical yields were between 15–42% (decay uncorrected) in 50–60 min. In vitro saturation and competition binding assays with human prostate cancer cells transfected with PSMA, PC3(+), indicated similar high nM binding affinities to PSMA for all radiotracers. In vivo biodistribution studies with positive control PC3(+) tumor xenografts showed that the kidneys had the highest uptake followed by tumors at 60 min. The PC3(+) tumor uptake was blocked with non-radioactive DCFPyL, and PC3(−) tumor xenograft (negative control) tumor uptake was negligible indicating that PSMA targeting was preserved. The most lipophilic tracer, [18F]2a, displayed comparable tumor-targeting to [18F]DCFPyL and a desirable alteration in pharmacokinetics and metabolism, resulting in significantly lower kidney uptake with a shift towards hepatobiliary clearance and increased liver uptake. Full article
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12 pages, 2127 KiB  
Article
Biodistribution of Intra-Arterial and Intravenous Delivery of Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles in a Rat Model to Guide Delivery Strategies for Diabetes Therapies
by Junfeng Li, Hirotake Komatsu, Erasmus K. Poku, Tove Olafsen, Kelly X. Huang, Lina A. Huang, Junie Chea, Nicole Bowles, Betty Chang, Jeffrey Rawson, Jiangling Peng, Anna M. Wu, John E. Shively and Fouad R. Kandeel
Pharmaceuticals 2022, 15(5), 595; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050595 - 12 May 2022
Cited by 7 | Viewed by 2129
Abstract
Umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) have become an emerging strategy for treating various autoimmune and metabolic disorders, particularly diabetes. Delivery of UC-MSC-EVs is essential to ensure optimal efficacy of UC-MSC-EVs. To develop safe and superior EVs-based delivery strategies, we explored [...] Read more.
Umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) have become an emerging strategy for treating various autoimmune and metabolic disorders, particularly diabetes. Delivery of UC-MSC-EVs is essential to ensure optimal efficacy of UC-MSC-EVs. To develop safe and superior EVs-based delivery strategies, we explored nuclear techniques including positron emission tomography (PET) to evaluate the delivery of UC-MSC-EVs in vivo. In this study, human UC-MSC-EVs were first successfully tagged with I-124 to permit PET determination. Intravenous (I.V.) and intra-arterial (I.A.) administration routes of [124I]I-UC-MSC-EVs were compared and evaluated by in vivo PET-CT imaging and ex vivo biodistribution in a non-diabetic Lewis (LEW) rat model. For I.A. administration, [124I]I-UC-MSC-EVs were directly infused into the pancreatic parenchyma via the celiac artery. PET imaging revealed that the predominant uptake occurred in the liver for both injection routes, and further imaging characterized clearance patterns of [124I]I-UC-MSC-EVs. For biodistribution, the uptake (%ID/gram) in the spleen was significantly higher for I.V. administration compared to I.A. administration (1.95 ± 0.03 and 0.43 ± 0.07, respectively). Importantly, the pancreas displayed similar uptake levels between the two modalities (0.20 ± 0.06 for I.V. and 0.24 ± 0.03 for I.A.). Therefore, our initial data revealed that both routes had similar delivery efficiency for [124I]I-UC-MSC-EVs except in the spleen and liver, considering that higher spleen uptake could enhance immunomodulatory application of UC-MSC-EVs. These findings could guide the development of safe and efficacious delivery strategies for UC-MSC-EVs in diabetes therapies, in which a minimally invasive I.V. approach would serve as a better delivery strategy. Further confirmation studies are ongoing. Full article
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12 pages, 3023 KiB  
Article
Pharmacokinetic Imaging Using 99mTc-Mebrofenin to Untangle the Pattern of Hepatocyte Transporter Disruptions Induced by Endotoxemia in Rats
by Solène Marie, Irene Hernández-Lozano, Marc Le Vée, Louise Breuil, Wadad Saba, Maud Goislard, Sébastien Goutal, Charles Truillet, Oliver Langer, Olivier Fardel and Nicolas Tournier
Pharmaceuticals 2022, 15(4), 392; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15040392 - 24 Mar 2022
Cited by 2 | Viewed by 2250
Abstract
Endotoxemia-induced inflammation may impact the activity of hepatocyte transporters, which control the hepatobiliary elimination of drugs and bile acids. 99mTc-mebrofenin is a non-metabolized substrate of transporters expressed at the different poles of hepatocytes. 99mTc-mebrofenin imaging was performed in rats after the [...] Read more.
Endotoxemia-induced inflammation may impact the activity of hepatocyte transporters, which control the hepatobiliary elimination of drugs and bile acids. 99mTc-mebrofenin is a non-metabolized substrate of transporters expressed at the different poles of hepatocytes. 99mTc-mebrofenin imaging was performed in rats after the injection of lipopolysaccharide (LPS). Changes in transporter expression were assessed using quantitative polymerase chain reaction of resected liver samples. Moreover, the particular impact of pharmacokinetic drug–drug interactions in the context of endotoxemia was investigated using rifampicin (40 mg/kg), a potent inhibitor of hepatocyte transporters. LPS increased 99mTc-mebrofenin exposure in the liver (1.7 ± 0.4-fold). Kinetic modeling revealed that endotoxemia did not impact the blood-to-liver uptake of 99mTc-mebrofenin, which is mediated by organic anion-transporting polypeptide (Oatp) transporters. However, liver-to-bile and liver-to-blood efflux rates were dramatically decreased, leading to liver accumulation. The transcriptomic profile of hepatocyte transporters consistently showed a downregulation of multidrug resistance-associated proteins 2 and 3 (Mrp2 and Mrp3), which mediate the canalicular and sinusoidal efflux of 99mTc-mebrofenin in hepatocytes, respectively. Rifampicin effectively blocked both the Oatp-mediated influx and the Mrp2/3-related efflux of 99mTc-mebrofenin. The additive impact of endotoxemia and rifampicin led to a 3.0 ± 1.3-fold increase in blood exposure compared with healthy non-treated animals. 99mTc-mebrofenin imaging is useful to investigate disease-associated change in hepatocyte transporter function. Full article
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13 pages, 2679 KiB  
Article
In Vivo Imaging of Rat Vascularity with FDG-Labeled Erythrocytes
by Shaowei Wang, Mikalai Budzevich, Mahmoud A. Abdalah, Yoganand Balagurunathan and Jung W. Choi
Pharmaceuticals 2022, 15(3), 292; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15030292 - 27 Feb 2022
Cited by 2 | Viewed by 2446
Abstract
Microvascular disease is frequently found in major pathologies affecting vital organs, such as the brain, heart, and kidneys. While imaging modalities, such as ultrasound, computed tomography, single photon emission computed tomography, and magnetic resonance imaging, are widely used to visualize vascular abnormalities, the [...] Read more.
Microvascular disease is frequently found in major pathologies affecting vital organs, such as the brain, heart, and kidneys. While imaging modalities, such as ultrasound, computed tomography, single photon emission computed tomography, and magnetic resonance imaging, are widely used to visualize vascular abnormalities, the ability to non-invasively assess an organ’s total vasculature, including microvasculature, is often limited or cumbersome. Previously, we have demonstrated proof of concept that non-invasive imaging of the total mouse vasculature can be achieved with 18F-fluorodeoxyglucose (18F-FDG)-labeled human erythrocytes and positron emission tomography/computerized tomography (PET/CT). In this work, we demonstrate that changes in the total vascular volume of the brain and left ventricular myocardium of normal rats can be seen after pharmacological vasodilation using 18F-FDG-labeled rat red blood cells (FDG RBCs) and microPET/CT imaging. FDG RBC PET imaging was also used to approximate the location of myocardial injury in a surgical myocardial infarction rat model. Finally, we show that FDG RBC PET imaging can detect relative differences in the degree of drug-induced intra-myocardial vasodilation between diabetic rats and normal controls. This FDG-labeled RBC PET imaging technique may thus be useful for assessing microvascular disease pathologies and characterizing pharmacological responses in the vascular bed of interest. Full article
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13 pages, 3959 KiB  
Article
Thin Layer-Protected Gold Nanoparticles for Targeted Multimodal Imaging with Photoacoustic and CT
by Jing Chen, Van Phuc Nguyen, Sangeeta Jaiswal, Xiaoyu Kang, Miki Lee, Yannis M. Paulus and Thomas D. Wang
Pharmaceuticals 2021, 14(11), 1075; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14111075 - 25 Oct 2021
Cited by 8 | Viewed by 2392
Abstract
The large size of nanoparticles prevents rapid extravasation from blood vessels and diffusion into tumors. Multimodal imaging uses the physical properties of one modality to validate the results of another. We aim to demonstrate the use of a targeted thin layer-protected ultra-small gold [...] Read more.
The large size of nanoparticles prevents rapid extravasation from blood vessels and diffusion into tumors. Multimodal imaging uses the physical properties of one modality to validate the results of another. We aim to demonstrate the use of a targeted thin layer-protected ultra-small gold nanoparticles (Au-NPs) to detect cancer in vivo using multimodal imaging with photoacoustic and computed tomography (CT). The thin layer was produced using a mixed thiol-containing short ligands, including MUA, CVVVT-ol, and HS-(CH2)11-PEG4-OH. The gold nanoparticle was labeled with a heterobivalent (HB) peptide ligand that targets overexpression of epidermal growth factor receptors (EGFR) and ErbB2, hereafter HB-Au-NPs. A human xenograft model of esophageal cancer was used for imaging. HB-Au-NPs show spherical morphology, a core diameter of 4.47 ± 0.8 nm on transmission electron microscopy, and a hydrodynamic diameter of 6.41 ± 0.73 nm on dynamic light scattering. Uptake of HB-Au-NPs was observed only in cancer cells that overexpressed EGFR and ErbB2 using photoacoustic microscopy. Photoacoustic images of tumors in vivo showed peak HB-Au-NPs uptake at 8 h post-injection with systemic clearance by ~48 h. Whole-body images using CT validated specific tumor uptake of HB-Au-NPs in vivo. HB-Au-NPs showed good stability and biocompatibility with fast clearance and contrast-enhancing capability for both photoacoustic and CT imaging. A targeted thin layer-protected gold nanoprobe represents a new platform for molecular imaging and shows promise for early detection and staging of cancer. Full article
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Review

Jump to: Editorial, Research

18 pages, 2903 KiB  
Review
Future Prospects of Positron Emission Tomography–Magnetic Resonance Imaging Hybrid Systems and Applications in Psychiatric Disorders
by Young-Don Son, Young-Bo Kim, Jong-Hoon Kim, Jeong-Hee Kim, Dae-Hyuk Kwon, Haigun Lee and Zang-Hee Cho
Pharmaceuticals 2022, 15(5), 583; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050583 - 08 May 2022
Cited by 4 | Viewed by 5199
Abstract
A positron emission tomography (PET)–magnetic resonance imaging (MRI) hybrid system has been developed to improve the accuracy of molecular imaging with structural imaging. However, the mismatch in spatial resolution between the two systems hinders the use of the hybrid system. As the magnetic [...] Read more.
A positron emission tomography (PET)–magnetic resonance imaging (MRI) hybrid system has been developed to improve the accuracy of molecular imaging with structural imaging. However, the mismatch in spatial resolution between the two systems hinders the use of the hybrid system. As the magnetic field of the MRI increased up to 7.0 tesla in the commercial system, the performance of the MRI system largely improved. Several technical attempts in terms of the detector and the software used with the PET were made to improve the performance. As a result, the high resolution of the PET–MRI fusion system enables quantitation of metabolism and molecular information in the small substructures of the brainstem, hippocampus, and thalamus. Many studies on psychiatric disorders, which are difficult to diagnose with medical imaging, have been accomplished using various radioligands, but only a few studies have been conducted using the PET–MRI fusion system. To increase the clinical usefulness of medical imaging in psychiatric disorders, a high-resolution PET–MRI fusion system can play a key role by providing important information on both molecular and structural aspects in the fine structures of the brain. The development of high-resolution PET–MR systems and their potential roles in clinical studies of psychiatric disorders were reviewed as prospective views in future diagnostics. Full article
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21 pages, 1500 KiB  
Review
Refining Glioblastoma Surgery through the Use of Intra-Operative Fluorescence Imaging Agents
by Oluwakanyinsolami Netufo, Kate Connor, Liam P. Shiels, Kieron J. Sweeney, Dan Wu, Donal F. O’Shea, Annette T. Byrne and Ian S. Miller
Pharmaceuticals 2022, 15(5), 550; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050550 - 29 Apr 2022
Cited by 6 | Viewed by 2663
Abstract
Glioblastoma (GBM) is the most aggressive adult brain tumour with a dismal 2-year survival rate of 26–33%. Maximal safe resection plays a crucial role in improving patient progression-free survival (PFS). Neurosurgeons have the significant challenge of delineating normal tissue from brain tumour to [...] Read more.
Glioblastoma (GBM) is the most aggressive adult brain tumour with a dismal 2-year survival rate of 26–33%. Maximal safe resection plays a crucial role in improving patient progression-free survival (PFS). Neurosurgeons have the significant challenge of delineating normal tissue from brain tumour to achieve the optimal extent of resection (EOR), with 5-Aminolevulinic Acid (5-ALA) the only clinically approved intra-operative fluorophore for GBM. This review aims to highlight the requirement for improved intra-operative imaging techniques, focusing on fluorescence-guided imaging (FGS) and the use of novel dyes with the potential to overcome the limitations of current FGS. The review was performed based on articles found in PubMed an.d Google Scholar, as well as articles identified in searched bibliographies between 2001 and 2022. Key words for searches included ‘Glioblastoma’ + ‘Fluorophore’+ ‘Novel’ + ‘Fluorescence Guided Surgery’. Current literature has favoured the approach of using targeted fluorophores to achieve specific accumulation in the tumour microenvironment, with biological conjugates leading the way. These conjugates target specific parts overexpressed in the tumour. The positive results in breast, ovarian and colorectal tissue are promising and may, therefore, be applied to intracranial neoplasms. Therefore, this design has the potential to produce favourable results in GBM by reducing the residual tumour, which translates to decreased tumour recurrence, morbidity and ultimately, mortality in GBM patients. Several preclinical studies have shown positive results with targeted dyes in distinguishing GBM cells from normal brain parenchyma, and targeted dyes in the Near-Infrared (NIR) emission range offer promising results, which may be valuable future alternatives. Full article
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17 pages, 819 KiB  
Review
Radiopharmaceutical Labelling for Lung Ventilation/Perfusion PET/CT Imaging: A Review of Production and Optimization Processes for Clinical Use
by Frédérique Blanc-Béguin, Simon Hennebicq, Philippe Robin, Raphaël Tripier, Pierre-Yves Salaün and Pierre-Yves Le Roux
Pharmaceuticals 2022, 15(5), 518; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050518 - 22 Apr 2022
Cited by 8 | Viewed by 2806
Abstract
Lung ventilation/perfusion (V/Q) positron emission tomography-computed tomography (PET/CT) is a promising imaging modality for regional lung function assessment. The same carrier molecules as a conventional V/Q scan (i.e., carbon nanoparticles for ventilation and macro aggregated albumin particles for perfusion) are used, but they [...] Read more.
Lung ventilation/perfusion (V/Q) positron emission tomography-computed tomography (PET/CT) is a promising imaging modality for regional lung function assessment. The same carrier molecules as a conventional V/Q scan (i.e., carbon nanoparticles for ventilation and macro aggregated albumin particles for perfusion) are used, but they are labeled with gallium-68 (68Ga) instead of technetium-99m (99mTc). For both radiopharmaceuticals, various production processes have been proposed. This article discusses the challenges associated with the transition from 99mTc- to 68Ga-labelled radiopharmaceuticals. The various production and optimization processes for both radiopharmaceuticals are reviewed and discussed for optimal clinical use. Full article
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25 pages, 4121 KiB  
Review
Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis: Translational Implications
by Ruiqing Ni
Pharmaceuticals 2021, 14(11), 1179; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14111179 - 18 Nov 2021
Cited by 10 | Viewed by 3776
Abstract
Animal models of Alzheimer’s disease amyloidosis that recapitulate cerebral amyloid-beta pathology have been widely used in preclinical research and have greatly enabled the mechanistic understanding of Alzheimer’s disease and the development of therapeutics. Comprehensive deep phenotyping of the pathophysiological and biochemical features in [...] Read more.
Animal models of Alzheimer’s disease amyloidosis that recapitulate cerebral amyloid-beta pathology have been widely used in preclinical research and have greatly enabled the mechanistic understanding of Alzheimer’s disease and the development of therapeutics. Comprehensive deep phenotyping of the pathophysiological and biochemical features in these animal models is essential. Recent advances in positron emission tomography have allowed the non-invasive visualization of the alterations in the brain of animal models and in patients with Alzheimer’s disease. These tools have facilitated our understanding of disease mechanisms and provided longitudinal monitoring of treatment effects in animal models of Alzheimer’s disease amyloidosis. In this review, we focus on recent positron emission tomography studies of cerebral amyloid-beta accumulation, hypoglucose metabolism, synaptic and neurotransmitter receptor deficits (cholinergic and glutamatergic system), blood–brain barrier impairment, and neuroinflammation (microgliosis and astrocytosis) in animal models of Alzheimer’s disease amyloidosis. We further propose the emerging targets and tracers for reflecting the pathophysiological changes and discuss outstanding challenges in disease animal models and future outlook in the on-chip characterization of imaging biomarkers towards clinical translation. Full article
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