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14 pages, 4268 KiB

Open AccessArticle

Imageological/Structural Study regarding the Improved Pharmacokinetics by ⁶⁸Ga-Labeled PEGylated PSMA Multimer in Prostate Cancer

by Huihui Zhang, Maohua Rao, Huayi Zhao, Jianli Ren, Lan Hao, Meng Zhong, Yue Chen, Xia Yang, Yue Feng and Gengbiao Yuan

Pharmaceuticals 2023, 16(4), 589; https://doi.org/10.3390/ph16040589 - 14 Apr 2023

Cited by 2 | Viewed by 1441

Abstract

PMSA (prostate-specific membrane antigen) is currently the most significant target for diagnosing and treating PCa (prostate cancer). Herein, we reported a series ⁶⁸Ga/¹⁷⁷Lu-labeled multimer PSMA tracer conjugating with PEG chain, including [⁶⁸Ga]Ga-DOTA-(1P-PEG₄), [⁶⁸Ga]Ga-DOTA-(2P-PEG₀ [...] Read more.

PMSA (prostate-specific membrane antigen) is currently the most significant target for diagnosing and treating PCa (prostate cancer). Herein, we reported a series ⁶⁸Ga/¹⁷⁷Lu-labeled multimer PSMA tracer conjugating with PEG chain, including [⁶⁸Ga]Ga-DOTA-(1P-PEG₄), [⁶⁸Ga]Ga-DOTA-(2P-PEG₀), [⁶⁸Ga]Ga-DOTA-(2P-PEG₄), and [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DOTA-(2P-PEG₄)₂, which showed an advantage of a multivalent effect and PEGylation to achieve higher tumor accumulation and faster kidney clearance. To figure out how structural optimizations based on a PSMA multimer and PEGylation influence the probe’s tumor-targeting ability, biodistribution, and metabolism, we examined PSMA molecular probes’ affinities to PC-3 PIP (PSMA-highly-expressed PC-3 cell line), and conducted pharmacokinetics analysis, biodistribution detection, small animal PET/CT, and SPECT/CT imaging. The results showed that PEG₄ and PSMA dimer optimizations enhanced the probes’ tumor-targeting ability in PC-3 PIP tumor-bearing mice models. Compared with the PSMA monomer, the PEGylated PSMA dimer reduced the elimination half-life in the blood and increased uptake in the tumor, and the biodistribution results were consistent with PET/CT imaging results. [⁶⁸Ga]Ga-DOTA-(2P-PEG₄)₂ exhibited higher tumor-to-organ ratios. When labeled by lutetium-177, relatively high accumulation of DOTA-(2P-PEG₄)₂ was still detected in PC-3 PIP tumor-bearing mice models after 48 h, indicating its prolonged tumor retention time. Given the superiority in imaging, simple synthetic processes, and structural stability, DOTA-(2P-PEG₄)₂ is expected to be a promising tumor-targeting diagnostic molecular probe in future clinical practice. Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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13 pages, 4475 KiB

Open AccessArticle

Inflammatory Immune Process and Depression-like Behavior in Hypothyroid Rats: A [¹⁸F] DPA-714 Micro Positron Emission Tomography Study

by Yizhen Wang, Aijuan Tian, Fang Zhang, Jing Yu and Jianer Ling

Pharmaceuticals 2023, 16(2), 279; https://doi.org/10.3390/ph16020279 - 13 Feb 2023

Cited by 2 | Viewed by 1306

Abstract

Hypothyroidism is closely related to mental disorders, mainly depression, through an as-yet-unknown mechanism. The cerebral inflammatory immune process has been implied to play a pivotal role in the onset of affective symptoms in several conditions. In order to gain insight into the mechanism [...] Read more.

Hypothyroidism is closely related to mental disorders, mainly depression, through an as-yet-unknown mechanism. The cerebral inflammatory immune process has been implied to play a pivotal role in the onset of affective symptoms in several conditions. In order to gain insight into the mechanism underlying the depressive behaviors in hypothyroid rats, brain microglial activation was evaluated using micro positron emission tomography imaging with a translocator protein (TSPO) radioligand. Hypothyroidism was induced in adult male Wistar rats by administration of 0.05% propylthiouracil in drinking water for five weeks. Open field, forced swimming and tail suspension tests were employed to evaluate the depressive behavior in hypothyroid rats, and the relationship between the behavioral changes and brain microglial activation was evaluated using [¹⁸F] DPA-714 micro positron emission tomography imaging. The open field test revealed significantly reduced first-minute activity and rearing behavior in the hypothyroid group, as well as significantly increased immobility in the forced swimming test and the tail suspension test. Hypothyroidism induced significantly increased microglial activation in the hippocampus. The radioligand uptake in the hippocampus correlated negatively with first-minute activity in the open field test (p < 0.05), and the radioligand uptake in the hippocampus correlated positively with changes in the immobility time in the forced swimming test and the tail suspension test (p < 0.05). Immunohistochemistry also confirmed the activation of microglia and inflammatory bodies in hypothyroid rats. The results indicate that hypothyroidism can induce depressive behavior in adult Wistar rats, microglial activation in the hippocampus plays an important role in the depressive behavior in hypothyroid rats and the inflammatory immune mechanism may underlie the behavioral abnormalities in thyroid dysfunction. Furthermore, the findings in the present study suggest there might be a common mechanism underlying depressive behavior in adult-onset hypothyroidism and depression. Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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26 pages, 2648 KiB

Open AccessFeature PaperArticle

Clickable C-Glycosyl Scaffold for the Development of a Dual Fluorescent and [¹⁸F]fluorinated Cyanine-Containing Probe and Preliminary In Vitro/Vivo Evaluation by Fluorescence Imaging

by Julen Ariztia, Kamal Jouad, Valérie Jouan-Hureaux, Julien Pierson, Charlotte Collet, Bertrand Kuhnast, Katalin Selmeczi, Cédric Boura, Sandrine Lamandé-Langle and Nadia Pellegrini Moïse

Pharmaceuticals 2022, 15(12), 1490; https://doi.org/10.3390/ph15121490 - 29 Nov 2022

Cited by 2 | Viewed by 2038

Abstract

Considering the individual characteristics of positron emission tomography (PET) and optical imaging (OI) in terms of sensitivity, spatial resolution, and tissue penetration, the development of dual imaging agents for bimodal PET/OI imaging is a growing field. A current major breakthrough in this field [...] Read more.

Considering the individual characteristics of positron emission tomography (PET) and optical imaging (OI) in terms of sensitivity, spatial resolution, and tissue penetration, the development of dual imaging agents for bimodal PET/OI imaging is a growing field. A current major breakthrough in this field is the design of monomolecular agent displaying both a radioisotope for PET and a fluorescent dye for OI. We took advantage of the multifunctionalities allowed by a clickable C-glycosyl scaffold to gather the different elements. We describe, for the first time, the synthesis of a cyanine-based dual PET/OI imaging probe based on a versatile synthetic strategy and its direct radiofluorination via [¹⁸F]F-C bond formation. The non-radioactive dual imaging probe coupled with two c(RGDfK) peptides was evaluated in vitro and in vivo in fluorescence imaging. The binding on α_vβ₃ integrin (IC₅₀ = 16 nM) demonstrated the efficiency of the dimeric structure and PEG linkers in maintaining the affinity. In vivo fluorescence imaging of U-87 MG engrafted nude mice showed a high tumor uptake (40- and 100-fold increase for orthotopic and ectopic brain tumors, respectively, compared to healthy brain). In vitro and in vivo evaluations and resection of the ectopic tumor demonstrated the potential of the conjugate in glioblastoma cancer diagnosis and image-guided surgery. Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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26 pages, 3705 KiB

Open AccessArticle

Radiosynthesis and Preclinical Evaluation of an ¹⁸F-Labeled Triazolopyridopyrazine-Based Inhibitor for Neuroimaging of the Phosphodiesterase 2A (PDE2A)

by Barbara Wenzel, Stefan R. Fritzsche, Magali Toussaint, Detlef Briel, Klaus Kopka, Peter Brust, Matthias Scheunemann and Winnie Deuther-Conrad

Pharmaceuticals 2022, 15(10), 1272; https://doi.org/10.3390/ph15101272 - 15 Oct 2022

Viewed by 1608

Abstract

The cyclic nucleotide phosphodiesterase 2A is an intracellular enzyme which hydrolyzes the secondary messengers cAMP and cGMP and therefore plays an important role in signaling cascades. A high expression in distinct brain areas as well as in cancer cells makes PDE2A an interesting [...] Read more.

The cyclic nucleotide phosphodiesterase 2A is an intracellular enzyme which hydrolyzes the secondary messengers cAMP and cGMP and therefore plays an important role in signaling cascades. A high expression in distinct brain areas as well as in cancer cells makes PDE2A an interesting therapeutic and diagnostic target for neurodegenerative and neuropsychiatric diseases as well as for cancer. Aiming at specific imaging of this enzyme in the brain with positron emission tomography (PET), a new triazolopyridopyrazine-based derivative (11) was identified as a potent PDE2A inhibitor (IC_50, _PDE2A = 1.99 nM; IC_{50, PDE10A} ~2000 nM) and has been radiofluorinated for biological evaluation. In vitro autoradiographic studies revealed that [¹⁸F]11 binds with high affinity and excellent specificity towards PDE2A in the rat brain. For the PDE2A-rich region nucleus caudate and putamen an apparent K_D value of 0.24 nM and an apparent B_max value of 16 pmol/mg protein were estimated. In vivo PET-MR studies in rats showed a moderate brain uptake of [¹⁸F]11 with a highest standardized uptake value (SUV) of 0.97. However, no considerable enrichment in PDE2A-specific regions in comparison to a reference region was detectable (SUV_{caudate putamen} = 0.51 vs. SUV_cerebellum = 0.40 at 15 min p.i.). Furthermore, metabolism studies revealed a considerable uptake of radiometabolites of [¹⁸F]11 in the brain (66% parent fraction at 30 min p.i.). Altogether, despite the low specificity and the blood–brain barrier crossing of radiometabolites observed in vivo, [¹⁸F]11 is a valuable imaging probe for the in vitro investigation of PDE2A in the brain and has potential as a lead compound for further development of a PDE2A-specific PET ligand for neuroimaging. Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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18 pages, 1638 KiB

Open AccessArticle

Automated Radiosynthesis, Preliminary In Vitro/In Vivo Characterization of OncoFAP-Based Radiopharmaceuticals for Cancer Imaging and Therapy

by Francesco Bartoli, Philip Elsinga, Luiza Reali Nazario, Aureliano Zana, Andrea Galbiati, Jacopo Millul, Francesca Migliorini, Samuele Cazzamalli, Dario Neri, Riemer H. J. A. Slart and Paola Anna Erba

Pharmaceuticals 2022, 15(8), 958; https://doi.org/10.3390/ph15080958 - 02 Aug 2022

Cited by 5 | Viewed by 2765

Abstract

FAP-targeted radiopharmaceuticals represent a breakthrough in cancer imaging and a viable option for therapeutic applications. OncoFAP is an ultra-high-affinity ligand of FAP with a dissociation constant of 680 pM. OncoFAP has been recently discovered and clinically validated for PET imaging procedures in patients [...] Read more.

FAP-targeted radiopharmaceuticals represent a breakthrough in cancer imaging and a viable option for therapeutic applications. OncoFAP is an ultra-high-affinity ligand of FAP with a dissociation constant of 680 pM. OncoFAP has been recently discovered and clinically validated for PET imaging procedures in patients with solid malignancies. While more and more clinical validation is becoming available, the need for scalable and robust procedures for the preparation of this new class of radiopharmaceuticals continues to increase. In this article, we present the development of automated radiolabeling procedures for the preparation of OncoFAP-based radiopharmaceuticals for cancer imaging and therapy. A new series of [⁶⁸Ga]Ga-OncoFAP, [¹⁷⁷Lu]Lu-OncoFAP and [¹⁸F]AlF-OncoFAP was produced with high radiochemical yields. Chemical and biochemical characterization after radiolabeling confirmed its excellent stability, retention of high affinity for FAP and absence of radiolysis by-products. The in vivo biodistribution of [¹⁸F]AlF-NOTA-OncoFAP, a candidate for PET imaging procedures in patients, was assessed in mice bearing FAP-positive solid tumors. The product showed rapid accumulation in solid tumors, with an average of 6.6% ID/g one hour after systemic administration and excellent tumor-to-healthy organs ratio. We have developed simple, quick, safe and robust synthetic procedures for the preparation of theranostic OncoFAP-compounds based on Gallium-68, Lutetium-177 and Fluorine-18 using the commercially available FASTlab synthesis module. Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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19 pages, 4084 KiB

Open AccessArticle

Longitudinal Consumption of Ergothioneine Reduces Oxidative Stress and Amyloid Plaques and Restores Glucose Metabolism in the 5XFAD Mouse Model of Alzheimer’s Disease

by Clayton A. Whitmore, Justin R. Haynes, William J. Behof, Adam J. Rosenberg, Mohammed N. Tantawy, Brian C. Hachey, Brian E. Wadzinski, Benjamin W. Spiller, Todd E. Peterson, Krista C. Paffenroth, Fiona E. Harrison, Robert B. Beelman, Printha Wijesinghe, Joanne A. Matsubara and Wellington Pham

Pharmaceuticals 2022, 15(6), 742; https://doi.org/10.3390/ph15060742 - 13 Jun 2022

Cited by 17 | Viewed by 4402

Abstract

Background: Ergothioneine (ERGO) is a unique antioxidant and a rare amino acid available in fungi and various bacteria but not in higher plants or animals. Substantial research data indicate that ERGO is a physiological antioxidant cytoprotectant. Different from other antioxidants that need to [...] Read more.

Background: Ergothioneine (ERGO) is a unique antioxidant and a rare amino acid available in fungi and various bacteria but not in higher plants or animals. Substantial research data indicate that ERGO is a physiological antioxidant cytoprotectant. Different from other antioxidants that need to breach the blood–brain barrier to enter the brain parenchyma, a specialized transporter called OCTN1 has been identified for transporting ERGO to the brain. Purpose: To assess whether consumption of ERGO can prevent the progress of Alzheimer’s disease (AD) on young (4-month-old) 5XFAD mice. Methods and materials: Three cohorts of mice were tested in this study, including ERGO-treated 5XFAD, non-treated 5XFAD, and WT mice. After the therapy, the animals went through various behavioral experiments to assess cognition. Then, mice were scanned with PET imaging to evaluate the biomarkers associated with AD using [¹¹C]PIB, [¹¹C]ERGO, and [¹⁸F]FDG radioligands. At the end of imaging, the animals went through cardiac perfusion, and the brains were isolated for immunohistology. Results: Young (4-month-old) 5XFAD mice did not show a cognitive deficit, and thus, we observed modest improvement in the treated counterparts. In contrast, the response to therapy was clearly detected at the molecular level. Treating 5XFAD mice with ERGO resulted in reduced amyloid plaques, oxidative stress, and rescued glucose metabolism. Conclusions: Consumption of high amounts of ERGO benefits the brain. ERGO has the potential to prevent AD. This work also demonstrates the power of imaging technology to assess response during therapy. Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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18 pages, 3541 KiB

Open AccessArticle

Quantitation of the A_2A Adenosine Receptor Density in the Striatum of Mice and Pigs with [¹⁸F]FLUDA by Positron Emission Tomography

by Daniel Gündel, Magali Toussaint, Thu Hang Lai, Winnie Deuther-Conrad, Paul Cumming, Susann Schröder, Rodrigo Teodoro, Rareş-Petru Moldovan, Francisco Pan-Montojo, Bernhard Sattler, Klaus Kopka, Osama Sabri and Peter Brust

Pharmaceuticals 2022, 15(5), 516; https://doi.org/10.3390/ph15050516 - 22 Apr 2022

Cited by 4 | Viewed by 2614

Abstract

The cerebral expression of the A_2A adenosine receptor (A_2AAR) is altered in neurodegenerative diseases such as Parkinson’s (PD) and Huntington’s (HD) diseases, making these receptors an attractive diagnostic and therapeutic target. We aimed to further investigate the pharmacokinetic properties in [...] Read more.

The cerebral expression of the A_2A adenosine receptor (A_2AAR) is altered in neurodegenerative diseases such as Parkinson’s (PD) and Huntington’s (HD) diseases, making these receptors an attractive diagnostic and therapeutic target. We aimed to further investigate the pharmacokinetic properties in the brain of our recently developed A_2AAR–specific antagonist radiotracer [¹⁸F]FLUDA. For this purpose, we retrospectively analysed dynamic PET studies of healthy mice and rotenone–treated mice, and conducted dynamic PET studies with healthy pigs. We performed analysis of mouse brain time–activity curves to calculate the mean residence time (MRT) by non–compartmental analysis, and the binding potential (BP_ND) of [¹⁸F]FLUDA using the simplified reference tissue model (SRTM). For the pig studies, we performed a Logan graphical analysis to calculate the radiotracer distribution volume (V_T) at baseline and under blocking conditions with tozadenant. The MRT of [¹⁸F]FLUDA in the striatum of mice was decreased by 30% after treatment with the A_2AAR antagonist istradefylline. Mouse results showed the highest BP_ND (3.9 to 5.9) in the striatum. SRTM analysis showed a 20% lower A_2AAR availability in the rotenone–treated mice compared to the control–aged group. Tozadenant treatment significantly decreased the V_T (14.6 vs. 8.5 mL · g⁻¹) and BP_ND values (1.3 vs. 0.3) in pig striatum. This study confirms the target specificity and a high BP_ND of [¹⁸F]FLUDA in the striatum. We conclude that [¹⁸F]FLUDA is a suitable tool for the non–invasive quantitation of altered A_2AAR expression in neurodegenerative diseases such as PD and HD, by PET. Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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17 pages, 2355 KiB

Open AccessEditor’s ChoiceArticle

A Convenient Route to New (Radio)Fluorinated and (Radio)Iodinated Cyclic Tyrosine Analogs

by Maria Noelia Chao, Jean-Michel Chezal, Eric Debiton, Damien Canitrot, Tiffany Witkowski, Sophie Levesque, Françoise Degoul, Sébastien Tarrit, Barbara Wenzel, Elisabeth Miot-Noirault, Audrey Serre and Aurélie Maisonial-Besset

Pharmaceuticals 2022, 15(2), 162; https://doi.org/10.3390/ph15020162 - 28 Jan 2022

Cited by 2 | Viewed by 2661

Abstract

The use of radiolabeled non-natural amino acids can provide high contrast SPECT/PET metabolic imaging of solid tumors. Among them, radiohalogenated tyrosine analogs (i.e., [¹²³I]IMT, [¹⁸F]FET, [¹⁸F]FDOPA, [¹²³I]8-iodo-L-TIC(OH), etc.) are of particular interest. While radioiodinated derivatives, [...] Read more.

The use of radiolabeled non-natural amino acids can provide high contrast SPECT/PET metabolic imaging of solid tumors. Among them, radiohalogenated tyrosine analogs (i.e., [¹²³I]IMT, [¹⁸F]FET, [¹⁸F]FDOPA, [¹²³I]8-iodo-L-TIC(OH), etc.) are of particular interest. While radioiodinated derivatives, such as [¹²³I]IMT, are easily available via electrophilic aromatic substitutions, the production of radiofluorinated aryl tyrosine analogs was a long-standing challenge for radiochemists before the development of innovative radiofluorination processes using arylboronate, arylstannane or iodoniums salts as precursors. Surprisingly, despite these methodological advances, no radiofluorinated analogs have been reported for [¹²³I]8-iodo-L-TIC(OH), a very promising radiotracer for SPECT imaging of prostatic tumors. This work describes a convenient synthetic pathway to obtain new radioiodinated and radiofluorinated derivatives of TIC(OH), as well as their non-radiolabeled counterparts. Using organotin compounds as key intermediates, [¹²⁵I]5-iodo-L-TIC(OH), [¹²⁵I]6-iodo-L-TIC(OH) and [¹²⁵I]8-iodo-L-TIC(OH) were efficiently prepared with good radiochemical yield (RCY, 51–78%), high radiochemical purity (RCP, >98%), molar activity (Am, >1.5–2.9 GBq/µmol) and enantiomeric excess (e.e. >99%). The corresponding [¹⁸F]fluoro-L-TIC(OH) derivatives were also successfully obtained by radiofluorination of the organotin precursors in the presence of tetrakis(pyridine)copper(II) triflate and nucleophilic [¹⁸F]F⁻ with 19–28% RCY d.c., high RCP (>98.9%), Am (20–107 GBq/µmol) and e.e. (>99%). Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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Review

Jump to: Research

14 pages, 869 KiB

Open AccessReview

Integrating Artificial Intelligence and PET Imaging for Drug Discovery: A Paradigm Shift in Immunotherapy

by Jeremy P. McGale, Harrison J. Howell, Arnaud Beddok, Mickael Tordjman, Roger Sun, Delphine Chen, Anna M. Wu, Tarek Assi, Samy Ammari and Laurent Dercle

Pharmaceuticals 2024, 17(2), 210; https://doi.org/10.3390/ph17020210 - 06 Feb 2024

Viewed by 1162

Abstract

The integration of artificial intelligence (AI) and positron emission tomography (PET) imaging has the potential to become a powerful tool in drug discovery. This review aims to provide an overview of the current state of research and highlight the potential for this alliance [...] Read more.

The integration of artificial intelligence (AI) and positron emission tomography (PET) imaging has the potential to become a powerful tool in drug discovery. This review aims to provide an overview of the current state of research and highlight the potential for this alliance to advance pharmaceutical innovation by accelerating the development and deployment of novel therapeutics. We previously performed a scoping review of three databases (Embase, MEDLINE, and CENTRAL), identifying 87 studies published between 2018 and 2022 relevant to medical imaging (e.g., CT, PET, MRI), immunotherapy, artificial intelligence, and radiomics. Herein, we reexamine the previously identified studies, performing a subgroup analysis on articles specifically utilizing AI and PET imaging for drug discovery purposes in immunotherapy-treated oncology patients. Of the 87 original studies identified, 15 met our updated search criteria. In these studies, radiomics features were primarily extracted from PET/CT images in combination (n = 9, 60.0%) rather than PET imaging alone (n = 6, 40.0%), and patient cohorts were mostly recruited retrospectively and from single institutions (n = 10, 66.7%). AI models were used primarily for prognostication (n = 6, 40.0%) or for assisting in tumor phenotyping (n = 4, 26.7%). About half of the studies stress-tested their models using validation sets (n = 4, 26.7%) or both validation sets and test sets (n = 4, 26.7%), while the remaining six studies (40.0%) either performed no validation at all or used less stringent methods such as cross-validation on the training set. Overall, the integration of AI and PET imaging represents a paradigm shift in drug discovery, offering new avenues for more efficient development of therapeutics. By leveraging AI algorithms and PET imaging analysis, researchers could gain deeper insights into disease mechanisms, identify new drug targets, or optimize treatment regimens. However, further research is needed to validate these findings and address challenges such as data standardization and algorithm robustness. Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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16 pages, 1017 KiB

Open AccessReview

Metabotropic Glutamate Receptor Subtype 5 Positron-Emission-Tomography Radioligands as a Tool for Central Nervous System Drug Development: Between Progress and Setbacks

by Anne-Claire Dupont, Nicolas Arlicot, Johnny Vercouillie, Sophie Serrière, Serge Maia, Frédérique Bonnet-Brilhault and Maria-Joao Santiago-Ribeiro

Pharmaceuticals 2023, 16(8), 1127; https://doi.org/10.3390/ph16081127 - 10 Aug 2023

Viewed by 1040

Abstract

The metabotropic glutamate receptor subtype 5 (mGluR5) is a class C G-protein-coupled receptor (GPCR) that has been implicated in various neuronal processes and, consequently, in several neuropsychiatric or neurodevelopmental disorders. Over the past few decades, mGluR5 has become a major focus for pharmaceutical [...] Read more.

The metabotropic glutamate receptor subtype 5 (mGluR5) is a class C G-protein-coupled receptor (GPCR) that has been implicated in various neuronal processes and, consequently, in several neuropsychiatric or neurodevelopmental disorders. Over the past few decades, mGluR5 has become a major focus for pharmaceutical companies, as an attractive target for drug development, particularly through the therapeutic potential of its modulators. In particular, allosteric binding sites have been targeted for better specificity and efficacy. In this context, Positron Emission Tomography (PET) appears as a useful tool for making decisions along a drug candidate’s development process, saving time and money. Thus, PET provides quantitative information about a potential drug candidate and its target at the molecular level. However, in this area, particular attention has to be given to the interpretation of the PET signal and its conclusions. Indeed, the complex pharmacology of both mGluR5 and radioligands, allosterism, the influence of endogenous glutamate and the choice of pharmacokinetic model are all factors that may influence the PET signal. This review focuses on mGluR5 PET radioligands used at several stages of central nervous system drug development, highlighting advances and setbacks related to the complex pharmacology of these radiotracers. Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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13 pages, 2983 KiB

Open AccessReview

Reactive Palladium–Ligand Complexes for ¹¹C-Carbonylation at Ambient Pressure: A Breakthrough in Carbon-11 Chemistry

by Kenneth Dahl, Anton Lindberg, Neil Vasdev and Magnus Schou

Pharmaceuticals 2023, 16(7), 955; https://doi.org/10.3390/ph16070955 - 03 Jul 2023

Viewed by 1498

Abstract

The Pd–Xantphos-mediated ¹¹C-carbonylation protocol (also known as the “Xantphos- method”), due to its simplistic and convenient nature, has facilitated researchers in meeting a longstanding need for preparing ¹¹C-carbonyl-labeled radiopharmaceuticals at ambient pressure for positron emission tomography (PET) imaging and drug discovery. [...] Read more.

The Pd–Xantphos-mediated ¹¹C-carbonylation protocol (also known as the “Xantphos- method”), due to its simplistic and convenient nature, has facilitated researchers in meeting a longstanding need for preparing ¹¹C-carbonyl-labeled radiopharmaceuticals at ambient pressure for positron emission tomography (PET) imaging and drug discovery. This development could be viewed as a breakthrough in carbon-11 chemistry, as evidenced by the rapid global adoption of the method by the pharmaceutical industry and academic laboratories worldwide. The method has been fully automated for the good manufacturing practice (GMP)-compliant production of novel radiopharmaceuticals for human use, and it has been adapted for “in-loop” reactions and microwave technology; an impressive number of ¹¹C-labeled compounds (>100) have been synthesized. Given the simplicity and efficiency of the method, as well as the abundance of carbonyl groups in bioactive drug molecules, we expect that this methodology will be even more widely adopted in future PET radiopharmaceutical research and drug development. Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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36 pages, 9565 KiB

Open AccessEditor’s ChoiceReview

Radiotracers for the Central Serotoninergic System

by Reynald Mangeant, Emmanuelle Dubost, Thomas Cailly and Valérie Collot

Pharmaceuticals 2022, 15(5), 571; https://doi.org/10.3390/ph15050571 - 03 May 2022

Cited by 1 | Viewed by 2874

Abstract

This review lists the most important radiotracers described so far for imaging the central serotoninergic system. Single-photon emission computed tomography and positron emission tomography radiotracers are reviewed and critically discussed for each receptor. Full article

(This article belongs to the Special Issue Alliance of PET/SPECT Imaging and Drug Design/Discovery for the Development of Novel Diagnostic or Therapeutic Tools)

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