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Technetium and Rhenium in Chemistry and Their Advanced Applications

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

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 44327

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Special Issue Editors

Dr. Cristina Bolzati

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Guest Editor

Institute of Condensed Matter Chemistry and Technologies for Energy/National Research Council, Corso Stati Uniti, 4, 35127 Padova, Italy
Interests: radiometals; coordination complexes; radiopharmaceuticals; radio-therapy; imaging agents; theranostics
Special Issues, Collections and Topics in MDPI journals

Dr. Debora Carpanese

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Guest Editor

Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35128 Padua, Italy
Interests: translational research; tumor immunology; drug delivery; pharmacology; molecular oncology; radiopharmaceuticals; tumor imaging; nuclear medicine

Dr. Laura Melendez-Alafort

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Guest Editor

Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, 35138 Padova, Italy
Interests: radiopharmaceutical chemistry; targeted radionuclide therapy; molecular imaging; PET and SPECT preclinical imaging; radiopharmacokinetics; endoradiotherapy; dosimetric studies
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Imaging and targeted therapy with radionuclides/radioactive probes continues to gain consensus in patient management, and to play an increasingly relevant role in precision medicine, where individuals can benefit from personalized treatments.

Despite the enhanced general emphasis on positron emission tomography (PET) technology, single photon emission computed tomography (SPECT) continues to be the first-line imaging modality in nuclear medicine. This is because SPECT imaging mostly relies on Technetium-99m (^99mTc), which, owing to its ideal physical decay properties, convenient availability, and rich and versatile coordination chemistry, still remains the most widely used radionuclide in clinical practice.

To add further value to this element is the existence of the radioactive rehenium-188 (¹⁸⁸Re) congener that, for its nuclear features, has been shown to be a very attractive candidate for endoradiotherapy application. The remarkable chemical similarities between technetium and rhenium, due to their position in the periodic table, result, for stable complexes characterized by equal molecular environments, in a similar biological behavior. This renders ^99mTc and ¹⁸⁸Re ideal for the development of a matching theranostic pair combining diagnosis and therapy.

However, looking at the ^99mTc/¹⁸⁸Re-radiopharmaceuticals scenario, it is evident that, although ^99mTc is the radionuclide of choice for SPECT, and a number of efficient approaches based on the Tc/Re-chemistry are available for the design and development of new target-specific radiopharmaceuticals, in the past two decades only a few new SPECT tracers have been approved by the FDA (Food Drug Administration) and/or the EMA (European Medicines Agency), and only a few re-labeled therapeutic agents have been investigated in early phase clinical trials for the management of primary tumors, bone metastasis and rheumatoid arthritis, pointing out a deadlock on the development of such classes of radiopharmaceuticals. Nevertheless, this fact can also be viewed as an incredible challenge and opportunity for researchers.

Over the last few years, the interruption of the global supply chain of reactor-produced ⁹⁹Mo needed for the production of ⁹⁹Mo/^99mTc generators has somehow brought out the key role of ^99mTc in clinical practice, forcing the scientific community to investigate alternative production routes for this important radionuclide. On the other hand, the recent advances in SPECT technology, which allow for rapid imaging acquisition, higher spatial resolution and sensitivity as compared to conventional anger-cameras, are gradually reducing the gap between SPECT and PET, also significantly changing the perspective of ^99mTc-housing radiopharmaceuticals and promoting the rediscovery and new imaging applications of this element after years of stagnation. In this situation, to fully exploit the potential of these new technologies, new categories of technetium complexes might be essential for opening a new era for this element.

This Special Issue is dedicated to all aspects of technetium and rhenium chemistry, and to the application of the corresponding radiometal-based compounds in radiopharmaceuticals applications as diagnostic, therapeutic or theranostic agents.

It is a pleasure to invite you to submit a manuscript to this Special Issue; articles and communications, as well as reviews, are all welcome.

Dr. Cristina Bolzati
Dr. Debora Carpanese
Dr. Laura Melendez-Alafort
Guest Editors

Manuscript Submission Information

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Keywords

Technetium
Technetium-99m
Rehenium
Rehenium-188/186
Coordination complexes
Technetium chemistry
Rehenium chemistry
Radiometals
Radiopharmaceuticals
Imaging agents
SPECT
Radiotherapy
Theranostics

Published Papers (11 papers)

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Research

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13 pages, 4944 KiB

Open AccessArticle

A Promising 1,3,5-Triazine-Based Anion Exchanger for Perrhenate Binding: Crystal Structures of Its Chloride, Nitrate and Perrhenate Salts

by Valery N. Zakharov, Pavel S. Lemport, Vladimir V. Chernyshev, Victor A. Tafeenko, Alexandr V. Yatsenko, Yuri A. Ustynyuk, Sergey F. Dunaev, Valentine G. Nenajdenko and Leonid A. Aslanov

Molecules 2023, 28(4), 1941; https://doi.org/10.3390/molecules28041941 - 17 Feb 2023

Cited by 2 | Viewed by 1549

Abstract

The reaction of pyridine with cyanuric chloride was studied under microwave activation as well as in the presence of silver nitrate. The product of hydrolysis containing two pyridinium rings and chloride anion was isolated. The structures of these anion exchanger salts with chloride, [...] Read more.

(This article belongs to the Special Issue Technetium and Rhenium in Chemistry and Their Advanced Applications)

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15 pages, 3948 KiB

Open AccessArticle

Evaluation of Rhenium and Technetium-99m Complexes Bearing Quinazoline Derivatives as Potential EGFR Agents

by Konstantina Makrypidi, Christos Kiritsis, Ioanna Roupa, Sotiria Triantopoulou, Antonio Shegani, Maria Paravatou-Petsotas, Aristeidis Chiotellis, Maria Pelecanou, Minas Papadopoulos and Ioannis Pirmettis

Molecules 2023, 28(4), 1786; https://doi.org/10.3390/molecules28041786 - 14 Feb 2023

Cited by 1 | Viewed by 1566

Abstract

Τhe Epidermal Growth Factor Receptor tyrosine kinase inhibitor (EGFR-TKI) 6-amino-4-[(3-bromophenyl) amino]quinazoline was derivatized with 6-bromohexanoyl-chloride and coupled with the tridentate chelating agents N-(2-pyridylmethyl) aminoethyl acetic acid (PAMA) and L(+)-cysteine bearing the donor atom set NNO and SNO, respectively. The rhenium precursors ReBr(CO)₅ and fac-[NEt₄]₂[ReBr₃(CO)₃] were used for the preparation of the Re complexes fac-[Re(NNO)(CO)₃] (5a) and fac-[Re(SNO)(CO)₃] (7a) which were characterized by NMR and IR spectroscopies. Subsequently, the new potential EGFR inhibitors were labeled with the fac-[^99mTc(CO)₃]⁺ core in high yield and radiochemical purity (>90%) by ligand exchange reaction using the fac-[^99mTc][Tc(OH₂)₃(CO)₃]⁺ precursor. The radiolabeled complexes were characterized by comparative HPLC analysis with the analogous rhenium (Re) complexes as references. In vitro studies in the A431 cell lines showed that both ligands and Re complexes inhibit A431 cell growth. Complex 5a demonstrated the highest potency (IC₅₀ = 8.85 ± 2.62 μM) and was further assessed for its capacity to inhibit EGFR autophosphorylation, presenting an IC₅₀ value of 26.11 nM. Biodistribution studies of the ^99mTc complexes in healthy mice showed high in vivo stability for both complexes and fast blood and soft tissue clearance with excretion occurring via the hepatobiliary system. Full article

(This article belongs to the Special Issue Technetium and Rhenium in Chemistry and Their Advanced Applications)

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18 pages, 2191 KiB

Open AccessArticle

Development and Evaluation of ^99mTc Tricarbonyl Complexes Derived from Flutamide with Affinity for Androgen Receptor

by María Elena Cardoso, Paula Decuadra, Maia Zeni, Agustín Delfino, Emilia Tejería, Fátima Coppe, Juan Manuel Mesa, Grysette Daher, Javier Giglio, Gonzalo Carrau, Daniela Gamenara, Omar Alonso, Mariella Terán and Ana Rey

Molecules 2023, 28(2), 820; https://doi.org/10.3390/molecules28020820 - 13 Jan 2023

Cited by 1 | Viewed by 1343

Abstract

With the objective to develop a potential ^99mTc radiopharmaceutical for imaging the androgen receptor (AR) in prostate cancer, four ligands bearing the same pharmacophore derived from the AR antagonist flutamide were prepared, labeled with ^99mTc, and their structures corroborated via comparison with the corresponding stable rhenium analogs. All complexes were obtained with high radiochemical purity. Three of the complexes were highly stable, and, due to their favorable physicochemical properties, were further evaluated using AR-positive and AR-negative cells in culture. All complexes exhibited considerable uptake in AR-positive cells, which could be blocked by an excess of flutamide. The efflux from the cells was moderate. They also showed significantly lower uptakes in AR-negative cells, indicating interactions with the AR receptor. However, the binding affinities were considerably reduced by the coordination to ^99mTc, and the complex that exhibited the best biological behavior did not show sufficient specificity towards AR-positive cells. Full article

(This article belongs to the Special Issue Technetium and Rhenium in Chemistry and Their Advanced Applications)

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17 pages, 2840 KiB

Open AccessEditor’s ChoiceArticle

The Chemistry of Phenylimidotechnetium(V) Complexes with Isocyanides: Steric and Electronic Factors

by Guilhem Claude, Laura Zeh, Maximilian Roca Jungfer, Adelheid Hagenbach, Joshua S. Figueroa and Ulrich Abram

Molecules 2022, 27(23), 8546; https://doi.org/10.3390/molecules27238546 - 4 Dec 2022

Cited by 5 | Viewed by 22076

Abstract

Organometallic approaches are of ongoing interest for the development of novel functional ^99mTc radiopharmaceuticals, while the basic organotechnetium chemistry seems frequently to be little explored. Thus, structural and reactivity studies with the long-lived isotope ⁹⁹Tc are of permanent interest as the foundation for further progress in the related radiopharmaceutical research with this artificial element. Particularly the knowledge about the organometallic chemistry of high-valent technetium compounds is scarcely developed. Here, phenylimido complexes of technetium(V) with different isocyanides are introduced. They have been synthesized by ligand-exchange procedures starting from [Tc(NPh)Cl₃(PPh₃)₂]. Different reactivity patterns and products have been obtained depending on the steric and electronic properties of the individual ligands. This involves the formation of 1:1 and 1:2 exchange products of Tc(V) with the general formulae [Tc(NPh)Cl₃(PPh₃)(isocyanide)], cis- or trans-[Tc(NPh)Cl₃(isocyanide)₂], but also the reduction in the metal and the formation of cationic technetium(I) complex of the formula [Tc(isocyanide)₆]⁺ when p-fluorophenyl isocyanide is used. The products have been studied by single-crystal X-ray diffraction and spectroscopic methods, including IR and multinuclear NMR spectroscopy. DFT calculations on the different isocyanides allow the prediction of their reactivity towards electron-rich and electron-deficient metal centers by means of the empirical SADAP parameter, which has been derived from the potential energy surface of the electron density on their potentially coordinating carbon atoms. Full article

(This article belongs to the Special Issue Technetium and Rhenium in Chemistry and Their Advanced Applications)

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21 pages, 4543 KiB

Open AccessArticle

Impact of Different [Tc(N)PNP]-Scaffolds on the Biological Properties of the Small cRGDfK Peptide: Synthesis, In Vitro and In Vivo Evaluations

by Nicola Salvarese, Debora Carpanese, Laura Meléndez-Alafort, Laura De Nardo, Andrea Calderan, Barbara Biondi, Paolo Ruzza, Antonio Rosato and Cristina Bolzati

Molecules 2022, 27(8), 2548; https://doi.org/10.3390/molecules27082548 - 14 Apr 2022

Cited by 3 | Viewed by 1703

Abstract

Background: The [^99mTc][Tc(N)(PNP)] system, where PNP is a bisphosphinoamine, is an interesting platform for the development of tumor ‘receptor-specific’ agents. Here, we compared the reactivity and impact of three [Tc(N)(PNP)] frameworks on the stability, receptor targeting properties, biodistribution, and metabolism of the corresponding [^99mTc][Tc(N)(PNP)]-tagged cRGDfK peptide to determine the best performing agent and to select the framework useful for the preparation of [^99mTc][Tc(N)(PNP)]-housing molecular targeting agents. Methods: cRGDfK pentapeptide was conjugated to Cys and labeled with each [Tc(N)(PNP)] framework. Radioconjugates were assessed for their lipophilicity, stability, in vitro and in vivo targeting properties, and performance. Results: All compounds were equally synthetically accessible and easy to purify (RCY ≥ 95%). The main influences of the synthon on the targeting peptide were observed in in vitro cell binding and in vivo. Conclusions: The variation in the substituents on the phosphorus atoms of the PNP enables a fine tuning of the biological features of the radioconjugates. ws[^99mTc][Tc(N)(PNP3OH)]– and [^99mTc][Tc(N)(PNP3)]– are better performing synthons in terms of labeling efficiency and in vivo performance than the [^99mTc][Tc(N)(PNP43)] framework and are therefore more suitable for further radiopharmaceutical purposes. Furthermore, the good labeling properties of the ws[^99mTc][Tc(N)(PNP3OH)]– framework can be exploited to extend this technology to the labeling of temperature-sensitive biomolecules suitable for SPECT imaging. Full article

(This article belongs to the Special Issue Technetium and Rhenium in Chemistry and Their Advanced Applications)

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18 pages, 4062 KiB

Open AccessArticle

Design, Synthesis and Preclinical Assessment of ^99mTc-iFAP for In Vivo Fibroblast Activation Protein (FAP) Imaging

by Diana Trujillo-Benítez, Myrna Luna-Gutiérrez, Guillermina Ferro-Flores, Blanca Ocampo-García, Clara Santos-Cuevas, Gerardo Bravo-Villegas, Enrique Morales-Ávila, Pedro Cruz-Nova, Lorenza Díaz-Nieto, Janice García-Quiroz, Erika Azorín-Vega, Antonio Rosato and Laura Meléndez-Alafort

Molecules 2022, 27(1), 264; https://doi.org/10.3390/molecules27010264 - 1 Jan 2022

Cited by 17 | Viewed by 3648

Abstract

Fibroblast activation protein (FAP) is expressed in the microenvironment of most human epithelial tumors. ⁶⁸Ga-labeled FAP inhibitors based on the cyanopyrrolidine structure (FAPI) are currently used for the detection of the tumor microenvironment by PET imaging. This research aimed to design, synthesize and preclinically evaluate a new FAP inhibitor radiopharmaceutical based on the ^99mTc-((R)-1-((6-hydrazinylnicotinoyl)-D-alanyl) pyrrolidin-2-yl) boronic acid (^99mTc-iFAP) structure for SPECT imaging. Molecular docking for affinity calculations was performed using the AutoDock software. The chemical synthesis was based on a series of coupling reactions of 6-hidrazinylnicotinic acid (HYNIC) and D-alanine to a boronic acid derivative. The iFAP was prepared as a lyophilized formulation based on EDDA/SnCl₂ for labeling with ^99mTc. The radiochemical purity (R.P.) was verified via ITLC-SG and reversed-phase radio-HPLC. The stability in human serum was evaluated by size-exclusion HPLC. In vitro cell uptake was assessed using N30 stromal endometrial cells (FAP positive) and human fibroblasts (FAP negative). Biodistribution and tumor uptake were determined in Hep-G2 tumor-bearing nude mice, from which images were acquired using a micro-SPECT/CT. The iFAP ligand (Ki = 0.536 nm, AutoDock affinity), characterized by UV-Vis, FT-IR, ¹H–NMR and UPLC-mass spectroscopies, was synthesized with a chemical purity of 92%. The ^99mTc-iFAP was obtained with a R.P. >98%. In vitro and in vivo studies indicated high radiotracer stability in human serum (>95% at 24 h), specific recognition for FAP, high tumor uptake (7.05 ± 1.13% ID/g at 30 min) and fast kidney elimination. The results found in this research justify additional dosimetric and clinical studies to establish the sensitivity and specificity of the ^99mTc-iFAP. Full article

(This article belongs to the Special Issue Technetium and Rhenium in Chemistry and Their Advanced Applications)

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14 pages, 3120 KiB

Open AccessArticle

Strategic Evaluation of the Traceless Staudinger Ligation for Radiolabeling with the Tricarbonyl Core

by Constantin Mamat, Christian Jentschel, Martin Köckerling and Jörg Steinbach

Molecules 2021, 26(21), 6629; https://doi.org/10.3390/molecules26216629 - 1 Nov 2021

Cited by 2 | Viewed by 2237

Abstract

The traceless Staudinger ligation with its two variants is a powerful biorthogonal conjugation method not only for the connection of biomolecules, but also for the introduction of fluorescence- or radiolabels under mild reaction conditions. Herein, the strategic evaluation of the traceless Staudinger ligation for radiolabeling ^99mTc using the fac-[Tc(CO)₃]⁺ core is presented. A convenient and high-yielding three-step synthetic procedure of dipicolylamine-based phosphanols as ligands for the mild radiolabeling was developed. The labeling was accomplished using a tricarbonyl kit and a ^99mTc-pertechnetate generator eluate showing 87% radiochemical conversion. The respective rhenium-based, non-radioactive reference compounds were synthesized using (Et₄N)₂[Re(CO)₃Br₃] as precursor. All products were analyzed by NMR, MS, and elemental analysis. Additional XRD analyses were performed. Full article

(This article belongs to the Special Issue Technetium and Rhenium in Chemistry and Their Advanced Applications)

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19 pages, 3751 KiB

Open AccessArticle

Common Shortcomings in Study on Radiopharmaceutical Design Research: A Case Study of ^99mTc-Labelled Methotrexate

by Przemysław Koźmiński, Paweł Krzysztof Halik, Raphael Chesori and Ewa Gniazdowska

Molecules 2021, 26(19), 5862; https://doi.org/10.3390/molecules26195862 - 27 Sep 2021

Cited by 1 | Viewed by 1942

Abstract

The aim of the work carried out was to draw attention to shortcomings that often appear at the stage of designing new radiopharmaceuticals. Based on a case study of ^99mTc-labelled methotrexate, this article describes frequent mistakes or misconceptions present not only in the referenced studies, but also in numerous radiopharmaceutical studies. The recommendations provided in this article highlight fundamental aspects of the credibility of radiopharmaceutical scientific research leading to the reliable results. Full article

(This article belongs to the Special Issue Technetium and Rhenium in Chemistry and Their Advanced Applications)

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15 pages, 3753 KiB

Open AccessEditor’s ChoiceArticle

New Bioconjugated Technetium and Rhenium Folates Synthesized by Transmetallation Reaction with Zinc Derivatives

by Jordi Borràs, Julie Foster, Roxana Kashani, Laura Meléndez-Alafort, Jane Sosabowski, Joan Suades and Ramon Barnadas-Rodríguez

Molecules 2021, 26(8), 2373; https://doi.org/10.3390/molecules26082373 - 19 Apr 2021

Cited by 3 | Viewed by 2214

Abstract

The zinc dithiocarbamates functionalized with folic acid 2_Zn and 3_Zn were synthesized with a simple straightforward method, using an appropriated folic acid derivative and a functionalized zinc dithiocarbamate (1_Zn). Zinc complexes 2_Zn and 3_Zn show very low solubilities in water, making them useful for preparing Tc-99m radiopharmaceuticals with a potentially high molar activity. Thus, the transmetallation reaction in water medium between the zinc complexes 2_Zn or 3_Zn and the cation fac-[^99mTc(H₂O)₃(CO)₃]⁺, in the presence of the monodentate ligand TPPTS, leads to the formation of the 2 + 1 complexes fac-[^99mTc(CO)₃(SS)(P)] bioconjugated to folic acid (2_Tc and 3_Tc). In spite of the low solubility of 2_Zn and 3_Zn in water, the reaction yield is higher than 95%, and the excess zinc reagent is easily removed by centrifugation. The Tc-99m complexes were characterized by comparing their HPLC with those of the homologous rhenium complexes (2_Re and 3_Re) previously synthesized and characterized by standard methods. Preliminary in vivo studies with 2_Tc and 3_Tc indicate low specific binding to folate receptors. In summary, Tc-99m folates 2_Tc and 3_Tc were prepared in high yields, using a one-pot transmetallation reaction with low soluble zinc dithiocarbamates (>1 ppm), at moderate temperature, without needing a subsequent purification step. Full article

(This article belongs to the Special Issue Technetium and Rhenium in Chemistry and Their Advanced Applications)

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11 pages, 2759 KiB

Open AccessArticle

Imaging Hydrogen Sulfide in Hypoxic Tissue with [^99mTc]Tc-Gluconate

by Yongkyoung Kweon, Ji-Yong Park, Young-Joo Kim, Yun-Sang Lee and Jae-Min Jeong

Molecules 2021, 26(1), 96; https://doi.org/10.3390/molecules26010096 - 28 Dec 2020

Cited by 3 | Viewed by 1916

Abstract

Hydrogen sulfide (H₂S) is the third gasotransmitter and is generated endogenously in hypoxic or inflammatory tissues and various cancers. We have recently demonstrated that endogenous H₂S can be imaged with [^99mTc]Tc-gluconate. In the present study, we detected H₂S generated in hypoxic tissue, both in vitro and in vivo, using [^99mTc]Tc-gluconate. In vitro uptake of [^99mTc]Tc-gluconate was measured under hypoxic and normoxic conditions, using the colon carcinoma cell line CT26, and was higher in hypoxic cells than that in normoxic cells. An acute hindlimb ischemia-reperfusion model was established in BALB/c mice by exposing the animals to 3 h of ischemia and 3 h of reperfusion prior to in vivo imaging. [^99mTc]Tc-gluconate (12.5 MBq) was intravenously injected through the tail vein, and uptake in the lower limb was analyzed by single-photon emission computed tomography/computed tomography (SPECT/CT). SPECT/CT images showed five times higher uptake in the ischemic limb than that in the normal limb. The standard uptake value (SUVmean) of the ischemic limb was 0.39 ± 0.03, while that of the normal limb was 0.07 ± 0.01. [^99mTc]Tc-gluconate is a novel imaging agent that can be used both in vitro and in vivo for the detection of endogenous H₂S generated in hypoxic tissue. Full article

(This article belongs to the Special Issue Technetium and Rhenium in Chemistry and Their Advanced Applications)

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Review

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20 pages, 3051 KiB

Open AccessReview

Fundamentals of Rhenium-188 Radiopharmaceutical Chemistry

by Janke Kleynhans, Adriano Duatti and Cristina Bolzati

Molecules 2023, 28(3), 1487; https://doi.org/10.3390/molecules28031487 - 3 Feb 2023

Cited by 6 | Viewed by 2336

Abstract

The β⁻ emitter, rhenium-188 (¹⁸⁸Re), has long been recognized as an attractive candidate for targeted cancer radionuclide therapy (TRNT). This transition metal shares chemical similarities with its congener element technetium, whose nuclear isomer technetium-99m (^99mTc) is the current workhorse of diagnostic nuclear medicine. The differences between these two elements have a significant impact on the radiolabelling methods and should always receive critical attention. This review aims to highlight what needs to be considered to design a successful radiopharmaceutical incorporating ¹¹⁸Re. Some of the most effective strategies for preparing therapeutic radiopharmaceuticals with ¹⁸⁸Re are illustrated and rationalized using the concept of the inorganic functional group (core) and a simple ligand field theoretical model combined with a qualitative definition of frontiers orbitals. Of special interest are the Re(V) oxo and Re(V) nitrido functional groups. Suitable ligands for binding to these cores are discussed, successful clinical applications are summarized, and a prediction of viable future applications is presented. Rhenium-188 decays through the emission of a high energy beta particle (2.12 MeV max energy) and a half-life of 16.9 h. An ideal biological target would therefore be a high-capacity target site (transporters, potential gradients, tumour microenvironment) with less emphasis on saturable targets such as overexpressed receptors on smaller metastases. Full article

(This article belongs to the Special Issue Technetium and Rhenium in Chemistry and Their Advanced Applications)

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