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Radiopharmaceuticals: From Design to Applications

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 16230

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Special Issue Editor

Dr. Aristeidis Chiotellis

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Guest Editor

National Center for Scientific Research “Demokritos”, Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, Agia Paraskevi, 15341 Athens, Greece
Interests: radiopharmaceutical chemistry; PET chemistry; technetium/rhenium chemistry; medicinal chemistry

Special Issue Information

Dear Colleagues,

Radiopharmaceuticals play a pivotal role in nuclear medicine, where they are widely used as diagnostic and therapeutic agents with their most important applications found in the understanding of neurodegenerative diseases, myocardial imaging, and the diagnosis and treatment of cancer.

In the era of personalized medicine, there is an ever-increasing need to develop efficacious strategies for the detection, molecular characterization, and therapy of disease while avoiding painful, inconvenient, expensive, or unnecessary methods and treatments. Undeniably, target-specific radiopharmaceuticals able to address a certain pathophysiological situation provide the means for real-time and pain-free visualization as well as molecular characterization and quantification of disease, which could in turn enable more effective and personalized therapy planning.

Therefore, there is an ever-increasing demand for the availability of diverse probes able to interrogate the in vivo biology of disease. In particular, for the potential impact of nuclear medicine in patient management and personalized medicine to be fully realized, there remains an urgent need to develop new radiopharmaceuticals for molecular targets of disease relevance that are not currently addressed while exhibiting optimal in vivo performance. Nevertheless, the development of the ‘’ideal’’ radiopharmaceutical is challenging since a plethora of issues need to be addressed such as selectivity and specificity for the molecular target in question, feasible chemistry for clinical applications, and optimal pharmacokinetic characteristics.

This Special Issue is dedicated to all efforts towards the development of target-specific radiopharmaceuticals aiming to address unmet clinical needs, as well as novel methodologies for the design and development of more effective radiopharmaceuticals with optimal in vivo performance.

Dr. Aristeidis Chiotellis
Guest Editor

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Keywords

radiopharmaceutical
targeted radionuclide therapy
nuclear medicine
pharmacokinetic
molecular targets
PET
radiochemistry
in vitro and in vivo studies
personalized medicine

Published Papers (6 papers)

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Research

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31 pages, 2418 KiB

Open AccessArticle

Optimizing the Safety and Efficacy of Bio-Radiopharmaceuticals for Cancer Therapy

by Cyprine Neba Funeh, Jessica Bridoux, Thomas Ertveldt, Timo W. M. De Groof, Dora Mugoli Chigoho, Parinaz Asiabi, Peter Covens, Matthias D’Huyvetter and Nick Devoogdt

Pharmaceutics 2023, 15(5), 1378; https://doi.org/10.3390/pharmaceutics15051378 - 30 Apr 2023

Cited by 2 | Viewed by 3556

Abstract

The precise delivery of cytotoxic radiation to cancer cells through the combination of a specific targeting vector with a radionuclide for targeted radionuclide therapy (TRT) has proven valuable for cancer care. TRT is increasingly being considered a relevant treatment method in fighting micro-metastases in the case of relapsed and disseminated disease. While antibodies were the first vectors applied in TRT, increasing research data has cited antibody fragments and peptides with superior properties and thus a growing interest in application. As further studies are completed and the need for novel radiopharmaceuticals nurtures, rigorous considerations in the design, laboratory analysis, pre-clinical evaluation, and clinical translation must be considered to ensure improved safety and effectiveness. Here, we assess the status and recent development of biological-based radiopharmaceuticals, with a focus on peptides and antibody fragments. Challenges in radiopharmaceutical design range from target selection, vector design, choice of radionuclides and associated radiochemistry. Dosimetry estimation, and the assessment of mechanisms to increase tumor uptake while reducing off-target exposure are discussed. Full article

(This article belongs to the Special Issue Radiopharmaceuticals: From Design to Applications)

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Graphical abstract

14 pages, 474 KiB

Open AccessArticle

A Multi-Criteria Decision Aid Tool for Radiopharmaceutical Selection in Tau PET Imaging

by Ilker Ozsahin, Efe Precious Onakpojeruo, Berna Uzun, Dilber Uzun Ozsahin and Tracy A. Butler

Pharmaceutics 2023, 15(4), 1304; https://doi.org/10.3390/pharmaceutics15041304 - 21 Apr 2023

Cited by 2 | Viewed by 1622

Abstract

The accumulation of pathologically misfolded tau is a feature shared by a group of neurodegenerative disorders collectively referred to as tauopathies. Alzheimer’s disease (AD) is the most prevalent of these tauopathies. Immunohistochemical evaluation allows neuropathologists to visualize paired-helical filaments (PHFs)—tau pathological lesions, but this is possible only after death and only shows tau in the portion of brain sampled. Positron emission tomography (PET) imaging allows both the quantitative and qualitative analysis of pathology over the whole brain of a living subject. The ability to detect and quantify tau pathology in vivo using PET can aid in the early diagnosis of AD, provide a way to monitor disease progression, and determine the effectiveness of therapeutic interventions aimed at reducing tau pathology. Several tau-specific PET radiotracers are now available for research purposes, and one is approved for clinical use. This study aims to analyze, compare, and rank currently available tau PET radiotracers using the fuzzy preference ranking organization method for enrichment of evaluations (PROMETHEE), which is a multi-criteria decision-making (MCDM) tool. The evaluation is based on relatively weighted criteria, such as specificity, target binding affinity, brain uptake, brain penetration, and rates of adverse reactions. Based on the selected criteria and assigned weights, this study shows that a second-generation tau tracer, [¹⁸F]RO-948, may be the most favorable. This flexible method can be extended and updated to include new tracers, additional criteria, and modified weights to help researchers and clinicians select the optimal tau PET tracer for specific purposes. Additional work is needed to confirm these results, including a systematic approach to defining and weighting criteria and clinical validation of tracers in different diseases and patient populations. Full article

(This article belongs to the Special Issue Radiopharmaceuticals: From Design to Applications)

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15 pages, 2927 KiB

Open AccessArticle

Rationalizing the Binding Modes of PET Radiotracers Targeting the Norepinephrine Transporter

by Anna Tutov, Xinyu Chen, Rudolf A. Werner, Saskia Mühlig, Thomas Zimmermann, Naoko Nose, Kazuhiro Koshino, Constantin Lapa, Michael Decker and Takahiro Higuchi

Pharmaceutics 2023, 15(2), 690; https://doi.org/10.3390/pharmaceutics15020690 - 17 Feb 2023

Viewed by 2143

Abstract

Purpose: A new PET radiotracer ¹⁸F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations of the structure–activity relationships (SARs) of NET-targeting radiotracers have rarely been performed. Methods: Without changing the phenethylguanidine pharmacophore and 3-fluoropropyl moiety that is crucial for easy labeling, six new analogs of ¹⁸F-AF78 with different meta-substituents on the benzene-ring were synthesized and evaluated in a competitive cellular uptake assay and in in vivo animal experiments in rats. Computational modeling of these tracers was established to quantitatively rationalize the interaction between the radiotracers and NET. Results: Using non-radiolabeled reference compounds, a competitive cellular uptake assay showed a decrease in NET-transporting affinity from meta-fluorine to iodine (0.42 and 6.51 µM, respectively), with meta-OH being the least active (22.67 µM). Furthermore, in vivo animal studies with radioisotopes showed that heart-to-blood ratios agreed with the cellular experiments, with AF78(F) exhibiting the highest cardiac uptake. This result correlates positively with the electronegativity rather than the atomic radius of the meta-substituent. Computational modeling studies revealed a crucial influence of halogen substituents on the radiotracer–NET interaction, whereby a T-shaped π–π stacking interaction between the benzene-ring of the tracer and the amino acid residues surrounding the NET binding site made major contributions to the different affinities, in accordance with the pharmacological data. Conclusion: The SARs were characterized by in vitro and in vivo evaluation, and computational modeling quantitatively rationalized the interaction between radiotracers and the NET binding site. These findings pave the way for further evaluation in different species and underline the potential of AF78(F) for clinical application, e.g., cardiac innervation imaging or molecular imaging of neuroendocrine tumors. Full article

(This article belongs to the Special Issue Radiopharmaceuticals: From Design to Applications)

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12 pages, 2649 KiB

Open AccessArticle

Radiolabeling and Biological Evaluation of Novel ^99mTc-Nitrido and ^99mTc-Oxo Complexes with 4-Methoxy-_L-Phenylalanine Dithiocarbamate for Tumor Imaging

by Guangxing Yin, Qing Ruan, Yuhao Jiang and Junbo Zhang

Pharmaceutics 2022, 14(10), 2196; https://doi.org/10.3390/pharmaceutics14102196 - 15 Oct 2022

Viewed by 1380

Abstract

To develop novel radiolabeled amino acid tumor imaging agents, 4-methoxy-_L-phenylalanine dithiocarbamate (MOPADTC) was synthesized successfully, and two kinds of ^99mTc-labeled complexes ([^99mTc]TcN-MOPADTC and [^99mTc]TcO-MOPADTC) with high radiochemical purities (RCP > 95%) were obtained. The in vitro stability and partition coefficient were determined, and the results show that both of these complexes have good in vitro stability; [^99mTc]TcO-MOPADTC is hydrophilic, while [^99mTc]TcN-MOPADTC is slightly lipophilic. The biodistribution of [^99mTc]TcN-MOPADTC and [^99mTc]TcO-MOPADTC in mice bearing S180 tumors shows that the tumor uptake and tumor/muscle ratio of [^99mTc]TcO-MOPADTC were higher than the tumor uptake and tumor/muscle ratio of [^99mTc]TcN-MOPADTC. In addition, the tumor retention of [^99mTc]TcO-MOPADTC is better than the tumor retention of [^99mTc]TcN-MOPADTC. A competitive inhibition assay was performed, and the results indicate that [^99mTc]TcO-MOPADTC may enter cells primarily via the _L-alanine/_L-serine/_L-cysteine (ASC) system. Single-photon emission computed tomography (SPECT) imaging of [^99mTc]TcO-MOPADTC shows obvious accumulation in tumor sites, suggesting that [^99mTc]TcO-MOPADTC is a novel potential tumor-imaging agent. Full article

(This article belongs to the Special Issue Radiopharmaceuticals: From Design to Applications)

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Review

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35 pages, 5105 KiB

Open AccessReview

²²⁵Ac-Labeled Somatostatin Analogs in the Management of Neuroendocrine Tumors: From Radiochemistry to Clinic

by Léa Rubira, Emmanuel Deshayes, Lore Santoro, Pierre Olivier Kotzki and Cyril Fersing

Pharmaceutics 2023, 15(4), 1051; https://doi.org/10.3390/pharmaceutics15041051 - 24 Mar 2023

Cited by 10 | Viewed by 3826

Abstract

The widespread use of peptide receptor radionuclide therapy (PRRT) represents a major therapeutic breakthrough in nuclear medicine, particularly since the introduction of ¹⁷⁷Lu-radiolabeled somatostatin analogs. These radiopharmaceuticals have especially improved progression-free survival and quality of life in patients with inoperable metastatic gastroenteropancreatic neuroendocrine tumors expressing somatostatin receptors. In the case of aggressive or resistant disease, the use of somatostatin derivatives radiolabeled with an alpha-emitter could provide a promising alternative. Among the currently available alpha-emitting radioelements, actinium-225 has emerged as the most suitable candidate, especially regarding its physical and radiochemical properties. Nevertheless, preclinical and clinical studies on these radiopharmaceuticals are still few and heterogeneous, despite the growing momentum for their future use on a larger scale. In this context, this report provides a comprehensive and extensive overview of the development of ²²⁵Ac-labeled somatostatin analogs; particular emphasis is placed on the challenges associated with the production of ²²⁵Ac, its physical and radiochemical properties, as well as the place of ²²⁵Ac–DOTATOC and ²²⁵Ac–DOTATATE in the management of patients with advanced metastatic neuroendocrine tumors. Full article

(This article belongs to the Special Issue Radiopharmaceuticals: From Design to Applications)

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35 pages, 4801 KiB

Open AccessReview

¹⁸F-Radiolabeled Translocator Protein (TSPO) PET Tracers: Recent Development of TSPO Radioligands and Their Application to PET Study

by Truong Giang Luu and Hee-Kwon Kim

Pharmaceutics 2022, 14(11), 2545; https://doi.org/10.3390/pharmaceutics14112545 - 21 Nov 2022

Cited by 10 | Viewed by 2762

Abstract

Translocator protein 18 kDa (TSPO) is a transmembrane protein in the mitochondrial membrane, which has been identified as a peripheral benzodiazepine receptor. TSPO is generally present at high concentrations in steroid-producing cells and plays an important role in steroid synthesis, apoptosis, and cell proliferation. In the central nervous system, TSPO expression is relatively modest under normal physiological circumstances. However, some pathological disorders can lead to changes in TSPO expression. Overexpression of TSPO is associated with several diseases, such as neurodegenerative diseases, neuroinflammation, brain injury, and cancers. TSPO has therefore become an effective biomarker of related diseases. Positron emission tomography (PET), a non-invasive molecular imaging technique used for the clinical diagnosis of numerous diseases, can detect diseases related to TSPO expression. Several radiolabeled TSPO ligands have been developed for PET. In this review, we describe recent advances in the development of TSPO ligands, and ¹⁸F-radiolabeled TSPO in particular, as PET tracers. This review covers pharmacokinetic studies, preclinical and clinical trials of ¹⁸F-labeled TSPO PET ligands, and the synthesis of TSPO ligands. Full article

(This article belongs to the Special Issue Radiopharmaceuticals: From Design to Applications)

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