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New Advances in Radiopharmaceutical Sciences: Chemistry and Applications
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New Advances in Radiopharmaceutical Sciences: Chemistry and Applications

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 27564

Special Issue Editors

Dr. António Paulo

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Guest Editor
C2TN- Centro de Ciências e Tecnologias Nucleares and DECN - Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
Interests: inorganic chemistry; medicinal chemistry; radiopharmaceutical chemistry; nuclear medicine; nanomedicine
Special Issues, Collections and Topics in MDPI journals
Dr. Filipa Fernandes Mendes

E-Mail Website1 Website2
Guest Editor
C2TN- Centro de Ciências e Tecnologias Nucleares and DECN - Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
Interests: molecular imaging; cancer theranostics; pre-clinical evaluation of radiopharmaceutical compounds; advanced cellular models

Special Issue Information

Dear Colleagues,

The development of radioactive molecules termed radiopharmaceuticals for diagnostic and/or therapeutic applications in nuclear medicine is a multidisciplinary and intense field of research that involves the contribution of different disciplines, such as chemistry, radiochemistry, biology, pharmacology and medicine. It has an important translational potential in the diagnosis and/or treatment of oncological, cardiovascular or neurodegenerative diseases, which can contribute for the rise of molecular and personalized medicine. The two fundamental nuclear medicine imaging techniques Single-Photon Emission Computed Tomography (SPECT) and the Positron Emission Tomography (PET) are nowadays essential for the diagnosis and follow-up of patients and can provide unique biological information, at molecular level, on healthy and pathological processes. On the other hand, therapeutic approaches using radionuclides are more scarce and still limited to the treatment of a few radiosensitive tumours. However, the unique possibility offered by radiopharmaceuticals of combining imaging and therapy in the same or related chemical entities holds great potential towards the development of more personalized approaches and patient-specific treatments, especially in cancer theranostics.

To take advantage of the favourable features of radiopharmaceuticals new chemical strategies for a specific and stable linkage of imaging or therapeutic radionuclides to a variety of targeting biomolecules are still needed. Such strategies must be well-fitted to the nature of the targeting biomolecule, while accounting for the chemical behaviour and decay properties of the radionuclide of interest that span from radiolahogens to d and f radiometals.   

This Special Issue of Molecules is open to papers (reviews, research papers, or communications) reporting recent developments in the field of radiopharmaceutical chemistry, focused in the design and evaluation of new chelators for labeling with radiometals (e.g. 99mTc, 68/67Ga ,177Lu or 225Ac) or new prosthestic groups for labeling with radiohalogens (e.g. 18F, 123I or 111At). Contributions on the design and preclinical evaluation of new target-specific radioconjugates (e.g. radiolabeled peptides or antibodies and their fragments) are also welcome, particularly those obtained using site-specific chemical biology approaches and inorganic or polymeric nanoparticles.

Dr. António Paulo
Dr. Filipa Fernandes Mendes
Guest Editors

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Keywords

  • Radiopharmaceuticals
  • Molecular Imaging
  • Theranostics
  • Radiometals
  • Radiohalogens
  • Radiolabelling Chemistry
  • Bifunctional Chelators
  • Prosthetic Groups
  • Chemical Biology

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Published Papers (7 papers)

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Research

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20 pages, 2876 KiB  
Article
Synthesis and In Vitro Comparison of DOTA, NODAGA and 15-5 Macrocycles as Chelators for the 64Cu-Labelling of Immunoconjugates
by Aurélie Maisonial-Besset, Tiffany Witkowski, Mercedes Quintana, Sophie Besse, Vincent Gaumet, Axel Cordonnier, Cyrille Alliot, Aurélien Vidal, Caroline Denevault-Sabourin, Sébastien Tarrit, Sophie Levesque, Elisabeth Miot-Noirault and Jean-Michel Chezal
Molecules 2023, 28(1), 75; https://doi.org/10.3390/molecules28010075 - 22 Dec 2022
Cited by 1 | Viewed by 3215
Abstract
The development of 64Cu-based immuno-PET radiotracers requires the use of copper-specific bifunctional chelators (BFCs) that contain functional groups allowing both convenient bioconjugation and stable copper complexes to limit in vivo bioreduction, transmetallation and/or transchelation. The excellent in vivo kinetic inertness of the [...] Read more.
The development of 64Cu-based immuno-PET radiotracers requires the use of copper-specific bifunctional chelators (BFCs) that contain functional groups allowing both convenient bioconjugation and stable copper complexes to limit in vivo bioreduction, transmetallation and/or transchelation. The excellent in vivo kinetic inertness of the pentaazamacrocyclic [64Cu]Cu-15-5 complex prompted us to investigate its potential for the 64Cu-labelling of monoclonal antibodies (mAbs), compared with the well-known NODAGA and DOTA chelators. To this end, three NODAGA, DOTA and 15-5-derived BFCs, containing a pendant azadibenzocyclooctyne moiety, were synthesised and a robust methodology was determined to form covalent bonds between them and azide-functionalised trastuzumab, an anti-HER2 mAb, using strain-promoted azide-alkyne cycloaddition. Unlike the DOTA derivative, the NODAGA- and 15-5-mAb conjugates were radiolabelled with 64Cu, obtaining excellent radiochemical yields, under mild conditions. Although all the radioimmunoconjugates showed excellent stability in PBS or mouse serum, [64Cu]Cu-15-5- and [64Cu]Cu-NODAGA-trastuzumab presented higher resistance to transchelation when challenged by EDTA. Finally, the immunoreactive fraction of the radioimmunoconjugates (88–94%) was determined in HER-2 positive BT474 human breast cancer cells, confirming that the bioconjugation and radiolabelling processes implemented had no significant impact on antigen recognition. Full article
(This article belongs to the Special Issue New Advances in Radiopharmaceutical Sciences: Chemistry and Applications)
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19 pages, 3861 KiB  
Article
Chelation of Theranostic Copper Radioisotopes with S-Rich Macrocycles: From Radiolabelling of Copper-64 to In Vivo Investigation
by Marianna Tosato, Marco Verona, Chiara Favaretto, Marco Pometti, Giordano Zanoni, Fabrizio Scopelliti, Francesco Paolo Cammarata, Luca Morselli, Zeynep Talip, Nicholas P. van der Meulen, Valerio Di Marco and Mattia Asti
Molecules 2022, 27(13), 4158; https://doi.org/10.3390/molecules27134158 - 28 Jun 2022
Cited by 11 | Viewed by 2795
Abstract
Copper radioisotopes are generally employed for cancer imaging and therapy when firmly coordinated via a chelating agent coupled to a tumor-seeking vector. However, the biologically triggered Cu2+-Cu+ redox switching may constrain the in vivo integrity of the resulting complex, leading [...] Read more.
Copper radioisotopes are generally employed for cancer imaging and therapy when firmly coordinated via a chelating agent coupled to a tumor-seeking vector. However, the biologically triggered Cu2+-Cu+ redox switching may constrain the in vivo integrity of the resulting complex, leading to demetallation processes. This unsought pathway is expected to be hindered by chelators bearing N, O, and S donors which appropriately complements the borderline-hard and soft nature of Cu2+ and Cu+. In this work, the labelling performances of a series of S-rich polyazamacrocyclic chelators with [64Cu]Cu2+ and the stability of the [64Cu]Cu-complexes thereof were evaluated. Among the chelators considered, the best results were obtained with 1,7-bis [2-(methylsulfanyl)ethyl]-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S). DO2A2S was labelled at high molar activities in mild reaction conditions, and its [64Cu]Cu2+ complex showed excellent integrity in human serum over 24 h. Biodistribution studies in BALB/c nude mice performed with [64Cu][Cu(DO2A2S)] revealed a behavior similar to other [64Cu]Cu-labelled cyclen derivatives characterized by high liver and kidney uptake, which could either be ascribed to transchelation phenomena or metabolic processing of the intact complex. Full article
(This article belongs to the Special Issue New Advances in Radiopharmaceutical Sciences: Chemistry and Applications)
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20 pages, 5157 KiB  
Article
Preliminary Assessment of the Anti-inflammatory Activity of New Structural Honokiol Analogs with a 4′-O-(2-Fluoroethyl) Moiety and the Potential of Their 18F-Labeled Derivatives for Neuroinflammation Imaging
by Daria D. Vaulina, Kira I. Stosman, Konstantin V. Sivak, Andrey G. Aleksandrov, Nikolai B. Viktorov, Nikolay N. Kuzmich, Mariia M. Kiseleva, Olga F. Kuznetsova and Natalia A. Gomzina
Molecules 2021, 26(21), 6630; https://doi.org/10.3390/molecules26216630 - 1 Nov 2021
Cited by 4 | Viewed by 2303
Abstract
Neolignans honokiol and 4′-O-methylhonokiol (MH) and their derivatives have pronounced anti-inflammatory activity, as evidenced by numerous pharmacological studies. Literature data suggested that cyclooxygenase type 2 (COX-2) may be a target for these compounds in vitro and in vivo. Recent studies of [...] Read more.
Neolignans honokiol and 4′-O-methylhonokiol (MH) and their derivatives have pronounced anti-inflammatory activity, as evidenced by numerous pharmacological studies. Literature data suggested that cyclooxygenase type 2 (COX-2) may be a target for these compounds in vitro and in vivo. Recent studies of [11C]MPbP (4′-[11C]methoxy-5-propyl-1,1′-biphenyl-2-ol) biodistribution in LPS (lipopolysaccharide)-treated rats have confirmed the high potential of MH derivatives for imaging neuroinflammation. Here, we report the synthesis of four structural analogs of honokiol, of which 4′-(2-fluoroethoxy)-2-hydroxy-5-propyl-1, 1′-biphenyl (F-IV) was selected for labeling with fluorine-18 (T1/2 = 109.8 min) due to its high anti-inflammatory activity confirmed by enzyme immunoassays (EIA) and neuromorphological studies. The high inhibitory potency of F-IV to COX-2 and its moderate lipophilicity and chemical stability are favorable factors for the preliminary evaluation of the radioligand [18F]F-IV in a rodent model of neuroinflammation. [18F]F-IV was prepared with good radiochemical yield and high molar activity and radiochemical purity by 18F-fluoroethylation of the precursor with Boc-protecting group (15) with [18F]2-fluoro-1-bromoethane ([18F]FEB). Ex vivo biodistribution studies revealed a small to moderate increase in radioligand uptake in the brain and peripheral organs of LPS-induced rats compared to control animals. Pretreatment with celecoxib resulted in significant blocking of radioactivity uptake in the brain (pons and medulla), heart, lungs, and kidneys, indicating that [18F]F-IV is likely to specifically bind to COX-2 in a rat model of neuroinflammation. However, in comparison with [11C]MPbP, the new radioligand showed decreased brain uptake in LPS rats and high retention in the blood pool, which apparently could be explained by its high plasma protein binding. We believe that the structure of [18F]F-IV can be optimized by replacing the substituents in the biphenyl core to eliminate these disadvantages and develop new radioligands for imaging activated microglia. Full article
(This article belongs to the Special Issue New Advances in Radiopharmaceutical Sciences: Chemistry and Applications)
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16 pages, 1349 KiB  
Article
A Semi Rigid Novel Hydroxamate AMPED-Based Ligand for 89Zr PET Imaging
by Lisa Russelli, Francesco De Rose, Loredana Leone, Sybille Reder, Markus Schwaiger, Calogero D’Alessandria and Lorenzo Tei
Molecules 2021, 26(19), 5819; https://doi.org/10.3390/molecules26195819 - 25 Sep 2021
Cited by 5 | Viewed by 2171
Abstract
In this work, we designed, developed, characterized, and investigated a new chelator and its bifunctional derivative for 89Zr labeling and PET-imaging. In a preliminary study, we synthesized two hexadentate chelators named AAZTHAS and AAZTHAG, based on the seven-membered heterocycle AMPED (6-amino-6-methylperhydro-1,4-diazepine) with [...] Read more.
In this work, we designed, developed, characterized, and investigated a new chelator and its bifunctional derivative for 89Zr labeling and PET-imaging. In a preliminary study, we synthesized two hexadentate chelators named AAZTHAS and AAZTHAG, based on the seven-membered heterocycle AMPED (6-amino-6-methylperhydro-1,4-diazepine) with the aim to increase the rigidity of the 89Zr complex by using N-methyl-N-(hydroxy)succinamide or N-methyl-N-(hydroxy)glutaramide pendant arms attached to the cyclic structure. N-methylhydroxamate groups are the donor groups chosen to efficiently coordinate 89Zr. After in vitro stability tests, we selected the chelator with longer arms, AAZTHAG, as the best complexing agent for 89Zr presenting a stability of 86.4 ± 5.5% in human serum (HS) for at least 72 h. Small animal PET/CT static scans acquired at different time points (up to 24 h) and ex vivo organ distribution studies were then carried out in healthy nude mice (n = 3) to investigate the stability and biodistribution in vivo of this new 89Zr-based complex. High stability in vivo, with low accumulation of free 89Zr in bones and kidneys, was measured. Furthermore, an activated ester functionalized version of AAZTHAG was synthesized to allow the conjugation with biomolecules such as antibodies. The bifunctional chelator was then conjugated to the human anti-HER2 monoclonal antibody Trastuzumab (Tz) as a proof of principle test of conjugation to biologically active molecules. The final 89Zr labeled compound was characterized via radio-HPLC and SDS-PAGE followed by autoradiography, and its stability in different solutions was assessed for at least 4 days. Full article
(This article belongs to the Special Issue New Advances in Radiopharmaceutical Sciences: Chemistry and Applications)
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20 pages, 6618 KiB  
Article
Au@Pt Core-Shell Nanoparticle Bioconjugates for the Therapy of HER2+ Breast Cancer and Hepatocellular Carcinoma. Model Studies on the Applicability of 193mPt and 195mPt Radionuclides in Auger Electron Therapy
by Kamil Wawrowicz, Agnieszka Majkowska-Pilip, Damian Gaweł, Ewelina Chajduk, Tadeusz Pieńkowski and Aleksander Bilewicz
Molecules 2021, 26(7), 2051; https://doi.org/10.3390/molecules26072051 - 3 Apr 2021
Cited by 16 | Viewed by 3184
Abstract
193mPt and 195mPt radionuclides are therapeutically attractive Auger electron emitters with notably high Auger electron yield per decay. The present paper summarizes the first step of research on the applications of core-shell (Au@Pt) nanoparticles for electron Auger therapy of HER2+ (human [...] Read more.
193mPt and 195mPt radionuclides are therapeutically attractive Auger electron emitters with notably high Auger electron yield per decay. The present paper summarizes the first step of research on the applications of core-shell (Au@Pt) nanoparticles for electron Auger therapy of HER2+ (human epidermal growth factor receptor 2) breast cancer and hepatocellular carcinoma. Gold nanoparticles (30 nm) were synthesized covered with a platinum shell at high efficiency (>80%) and were further evaluated for in vitro studies such as binding affinity, internalization and cytotoxicity. To find the mechanism(s) responsible for platinum cytotoxicity in HepG2 cells, the platinum concentration in isolated cell nuclei and cytoplasm was determined using ICP-MS (inductively coupled plasma mass spectrometry). Lack of platinum in cell nuclei suggests that the cytotoxic effect is associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Studies carried out on the SKOV-3 cell line with the use of a synthesized targeting bioconjugate (Au@Pt-PEG-trastuzumab) revealed a high affinity of this preparation to HER2+ cells, its internalization, its placement in the perinuclear area and partial intranuclear location. The specific binding for HER2 negative cells, MDA-MB-231, was negligible and Au@Pt-PEG-trastuzumab did not enter these cells. The results obtained are promising and warrant future investigation of Auger electron therapy using 193mPt and 195mPt based radiopharmaceuticals. Full article
(This article belongs to the Special Issue New Advances in Radiopharmaceutical Sciences: Chemistry and Applications)
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Review

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34 pages, 4242 KiB  
Review
The Chemical Scaffold of Theranostic Radiopharmaceuticals: Radionuclide, Bifunctional Chelator, and Pharmacokinetics Modifying Linker
by Holis Abdul Holik, Faisal Maulana Ibrahim, Angela Alysia Elaine, Bernap Dwi Putra, Arifudin Achmad and Achmad Hussein Sundawa Kartamihardja
Molecules 2022, 27(10), 3062; https://doi.org/10.3390/molecules27103062 - 10 May 2022
Cited by 30 | Viewed by 8763
Abstract
Therapeutic radiopharmaceuticals have been researched extensively in the last decade as a result of the growing research interest in personalized medicine to improve diagnostic accuracy and intensify intensive therapy while limiting side effects. Radiometal-based drugs are of substantial interest because of their greater [...] Read more.
Therapeutic radiopharmaceuticals have been researched extensively in the last decade as a result of the growing research interest in personalized medicine to improve diagnostic accuracy and intensify intensive therapy while limiting side effects. Radiometal-based drugs are of substantial interest because of their greater versatility for clinical translation compared to non-metal radionuclides. This paper comprehensively discusses various components commonly used as chemical scaffolds to build radiopharmaceutical agents, i.e., radionuclides, pharmacokinetic-modifying linkers, and chelators, whose characteristics are explained and can be used as a guide for the researcher. Full article
(This article belongs to the Special Issue New Advances in Radiopharmaceutical Sciences: Chemistry and Applications)
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19 pages, 2368 KiB  
Review
Advances in Radiopharmaceutical Sciences for Vascular Inflammation Imaging: Focus on Clinical Applications
by Kevin Prigent and Jonathan Vigne
Molecules 2021, 26(23), 7111; https://doi.org/10.3390/molecules26237111 - 24 Nov 2021
Cited by 3 | Viewed by 2968
Abstract
Biomedical imaging technologies offer identification of several anatomic and molecular features of disease pathogenesis. Molecular imaging techniques to assess cellular processes in vivo have been useful in advancing our understanding of several vascular inflammatory diseases. For the non-invasive molecular imaging of vascular inflammation, [...] Read more.
Biomedical imaging technologies offer identification of several anatomic and molecular features of disease pathogenesis. Molecular imaging techniques to assess cellular processes in vivo have been useful in advancing our understanding of several vascular inflammatory diseases. For the non-invasive molecular imaging of vascular inflammation, nuclear medicine constitutes one of the best imaging modalities, thanks to its high sensitivity for the detection of probes in tissues. 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) is currently the most widely used radiopharmaceutical for molecular imaging of vascular inflammatory diseases such as atherosclerosis and large-vessel vasculitis. The combination of [18F]FDG and positron emission tomography (PET) imaging has become a powerful tool to identify and monitor non-invasively inflammatory activities over time but suffers from several limitations including a lack of specificity and avid background in different localizations. The use of novel radiotracers may help to better understand the underlying pathophysiological processes and overcome some limitations of [18F]FDG PET for the imaging of vascular inflammation. This review examines how [18F]FDG PET has given us deeper insight into the role of inflammation in different vascular pathologies progression and discusses perspectives for alternative radiopharmaceuticals that could provide a more specific and simple identification of pathologies where vascular inflammation is implicated. Use of these novel PET tracers could lead to a better understanding of underlying disease mechanisms and help inform the identification and stratification of patients for newly emerging immune-modulatory therapies. Future research is needed to realize the true clinical translational value of PET imaging in vascular inflammatory diseases. Full article
(This article belongs to the Special Issue New Advances in Radiopharmaceutical Sciences: Chemistry and Applications)
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