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Targets, Tracers and Translation, Part 2 - New Horizons in...
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Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 86766

Special Issue Editor

Prof. Dr. Gerald Reischl

E-Mail Website
Guest Editor
1. Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, Tübingen, Germany
2. Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
Interests: radiopharmaceutical sciences; PET isotope production methods; PET tracer development; small molecules; antibodies and fragments; imaging of hypoxia/inflammation/infectious diseases; preclinical evaluation and translation into clinical application
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Dear Radiopharmaceutical Community,

Two years have passed since our first Special Issue on “Targets, Tracers and Translation”. In the meantime, the journal was indexed by SCIE with an impressive IF of 4.286 for 2019. As the first Special Issue was a remarkable success, it has now been decided that the right time has arrived to open a Part 2.

Radiopharmaceutical Sciences have impressively demonstrated their innovative power over the last few years to move nuclear medicine forward. The question of what comes beyond [18F]FDG can definitely be put to the archives. The global story of success of PSMA PET imaging and endoradiotherapy is the best example, and more targets of interest have been defined and tracer developments for a highly specific imaging have shown promising results. Imaging of, for example, senescence, cellular stress or specific receptors (e.g., CXCR4) in oncology offers new perspectives for therapy planning and control. Immunoimaging of therapy responses of tumors (e.g., CD4, CD8 or CD69 activation) is another highlight in the attempts at improving individual patient management. Of course, recent developments are not limited to oncology—there is also significant progress in the imaging of infectious diseases or in neurosciences, here especially to specifically image beta-amyloid plaques, tau or alpha-synuclein proteins or TSPO in neuro degeneration.

Additionally, successful attempts to broaden the availability of, so far, less common radionuclides for imaging and therapy have to be mentioned. The possibilities of production of extremely high amounts of [18F]fluoride in new target systems for cyclotrons, the availability of gallium-68 from the cyclotron, overcoming limitations of the generator, and also a wider availability of other cyclotron produced radionuclides such as scandium-43 and -44, copper-61 or copper-64, and zirconium-89 with longer half-lives open new perspectives in tracer design. For therapy, in addition to the currently widely used lutetium-177, alpha emitters such as actinium-225 have become available and broaden the spectra.

Recently, total-body PET scanners have started to break into the market. This will help to reduce radiation doses given to patients with longer-lived isotopes and facilitate their usage. At the same time, total-body PET offers a new entrance into radiopharmaceutical research on novel classes of radiotracers.

With this Special Issue, we want to illustrate and highlight the variety in recent radiopharmaceutical developments and the new horizons that are opened toward a broad spectrum of applications. The final goal of these developments, of course, the successful translation into the clinics and into nuclear medicine practice, should always be the focus.

We cordially invite you to participate in this Special Issue, “Targets, Tracers and Translation, Part 2—New Horizons in Radiopharmaceutical Development” and are excited to receive your latest successful results and share them with the community. In addition to original works, reviews are very welcome, as well.

PD Dr. Gerald Reischl
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • novel radiopharmaceuticals
  • radionuclides
  • molecular imaging
  • endoradiotherapy
  • oncology
  • immunology
  • neurology

Published Papers (27 papers)

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16 pages, 1720 KiB  
Article
Synthesis, Physicochemical, Labeling and In Vivo Characterization of 44Sc-Labeled DO3AM-NI as a Hypoxia-Sensitive PET Probe
by Dániel Szücs, Tibor Csupász, Judit P. Szabó, Adrienn Kis, Barbara Gyuricza, Viktória Arató, Viktória Forgács, Adrienn Vágner, Gábor Nagy, Ildikó Garai, Dezső Szikra, Imre Tóth, György Trencsényi, Gyula Tircsó and Anikó Fekete
Pharmaceuticals 2022, 15(6), 666; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15060666 - 26 May 2022
Cited by 2 | Viewed by 1620
Abstract
Hypoxia promotes angiogenesis, which is crucial for tumor growth, and induces malignant progression and increases the therapeutic resistance. Positron emission tomography (PET) enables the detection of the hypoxic regions in tumors using 2-nitroimidazole-based radiopharmaceuticals. We describe here a physicochemical study of the Sc(DO3AM-NI) [...] Read more.
Hypoxia promotes angiogenesis, which is crucial for tumor growth, and induces malignant progression and increases the therapeutic resistance. Positron emission tomography (PET) enables the detection of the hypoxic regions in tumors using 2-nitroimidazole-based radiopharmaceuticals. We describe here a physicochemical study of the Sc(DO3AM-NI) complex, which indicates: (a) relatively slow formation of the Sc(DO3AM-NI) chelate in acidic solution; (b) lower thermodynamic stability than the reference Sc(DOTA); (c) however, it is substantially more inert and consequently can be regarded as an excellent Sc-binder system. In addition, we report a comparison of 44Sc-labeled DO3AM-NI with its known 68Ga-labeled analog as a hypoxia PET probe. The in vivo and ex vivo biodistributions of 44Sc- and 68Ga-labeled DO3AM-NI in healthy and KB tumor-bearing SCID mice were examined 90 and 240 min after intravenous injection. No significant difference was found between the accumulation of 44Sc- and 68Ga-labeled DO3AM-NI in KB tumors. However, a significantly higher accumulation of [68Ga]Ga(DO3AM-NI) was found in liver, spleen, kidney, intestine, lung, heart and brain than for [44Sc]Sc(DO3AM-NI), leading to a lower tumor/background ratio. The tumor-to-muscle (T/M) ratio of [44Sc]Sc(DO3AM-NI) was approximately 10–15-fold higher than that of [68Ga]Ga(DO3AM-NI) at all time points. Thus, [44Sc]Sc(DO3AM-NI) allows the visualization of KB tumors with higher resolution, making it a promising hypoxia-specific PET radiotracer. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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28 pages, 2687 KiB  
Article
Development of 18F-Labeled Bispyridyl Tetrazines for In Vivo Pretargeted PET Imaging
by Rocío García-Vázquez, Jesper Tranekjær Jørgensen, Klas Erik Bratteby, Vladimir Shalgunov, Lars Hvass, Matthias M. Herth, Andreas Kjær and Umberto Maria Battisti
Pharmaceuticals 2022, 15(2), 245; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15020245 - 18 Feb 2022
Cited by 15 | Viewed by 2671
Abstract
Pretargeted PET imaging is an emerging and fast-developing method to monitor immuno-oncology strategies. Currently, tetrazine ligation is considered the most promising bioorthogonal reaction for pretargeting in vivo. Recently, we have developed a method to 18F-label ultrareactive tetrazines by copper-mediated fluorinations. However, bispyridyl [...] Read more.
Pretargeted PET imaging is an emerging and fast-developing method to monitor immuno-oncology strategies. Currently, tetrazine ligation is considered the most promising bioorthogonal reaction for pretargeting in vivo. Recently, we have developed a method to 18F-label ultrareactive tetrazines by copper-mediated fluorinations. However, bispyridyl tetrazines—one of the most promising structures for in vivo pretargeted applications—were inaccessible using this strategy. We believed that our successful efforts to 18F-label H-tetrazines using low basic labeling conditions could also be used to label bispyridyl tetrazines via aliphatic nucleophilic substitution. Here, we report the first direct 18F-labeling of bispyridyl tetrazines, their optimization for in vivo use, as well as their successful application in pretargeted PET imaging. This strategy resulted in the design of [18F]45, which could be labeled in a satisfactorily radiochemical yield (RCY = 16%), molar activity (Am = 57 GBq/µmol), and high radiochemical purity (RCP > 98%). The [18F]45 displayed a target-to-background ratio comparable to previously successfully applied tracers for pretargeted imaging. This study showed that bispyridyl tetrazines can be developed into pretargeted imaging agents. These structures allow an easy chemical modification of 18F-labeled tetrazines, paving the road toward highly functionalized pretargeting tools. Moreover, bispyridyl tetrazines led to near-instant drug release of iTCO-tetrazine-based ‘click-to-release’ reactions. Consequently, 18F-labeled bispyridyl tetrazines bear the possibility to quantify such release in vivo in the future. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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11 pages, 1546 KiB  
Article
Methods for the Determination of Transition Metal Impurities in Cyclotron-Produced Radiometals
by Viktória Forgács, Anikó Fekete, Barbara Gyuricza, Dániel Szücs, György Trencsényi and Dezső Szikra
Pharmaceuticals 2022, 15(2), 147; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15020147 - 26 Jan 2022
Cited by 2 | Viewed by 2940
Abstract
Cyclotron-produced radiometals must be separated from the irradiated target and purified from other metal impurities, which could interfere with the radiolabeling process. We compared different chromatographic and colorimetric methods to determine the amount of transition metals in radioactive samples. Besides commercially available colorimetric [...] Read more.
Cyclotron-produced radiometals must be separated from the irradiated target and purified from other metal impurities, which could interfere with the radiolabeling process. We compared different chromatographic and colorimetric methods to determine the amount of transition metals in radioactive samples. Besides commercially available colorimetric tests, 4-(2-pyridylazo)resorcinol and xylenol orange were used as a non-selective metal reagents, forming water-soluble chelates with most of the transition metals immediately. We compared the applicability of pre- and post-column derivatization, as well as colorimetric determination without separation. The studied chromatographic and colorimetric analyses are not suitable to completely replace atomic spectroscopic techniques for the determination of metal contaminants in radioactive samples, but they may play an important role in the development of methods for the purification of radiometals and in their routine quality control. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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16 pages, 3792 KiB  
Article
Comparative Evaluation of Radiochemical and Biological Properties of 131I- and [99mTc]Tc(CO)3-Labeled RGD Analogues Planned to Interact with the αvβ3 Integrin Expressed in Glioblastoma
by Danielle V. Sobral, Leonardo L. Fuscaldi, Ana Claudia R. Durante, Fernanda F. Mendonça, Larissa R. de Oliveira, Ana Cláudia C. Miranda, Jorge Mejia, Wagner R. Montor, Marycel F. de Barboza and Luciana Malavolta
Pharmaceuticals 2022, 15(2), 116; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15020116 - 18 Jan 2022
Cited by 4 | Viewed by 2173
Abstract
Radiolabeled peptides with high specificity for overexpressed receptors in tumor cells hold great promise for diagnostic and therapeutic applications. In this work, we aimed at comparing the radiolabeling efficiency and biological properties of two different RGD analogs: GRGDYV and GRGDHV, labeled with iodine-131 [...] Read more.
Radiolabeled peptides with high specificity for overexpressed receptors in tumor cells hold great promise for diagnostic and therapeutic applications. In this work, we aimed at comparing the radiolabeling efficiency and biological properties of two different RGD analogs: GRGDYV and GRGDHV, labeled with iodine-131 (131I) and technetium-99m-tricarbonyl complex [99mTc][Tc(CO)3]+. Additionally, we evaluated their interaction with the αvβ3 integrin molecule, overexpressed in a wide variety of tumors, including glioblastoma. Both peptides were chemically synthesized, purified and radiolabeled with 131I and [99mTc][Tc(CO)3]+ using the chloramine-T and tricarbonyl methodologies, respectively. The stability, binding to serum proteins and partition coefficient were evaluated for both radioconjugates. In addition, the binding and internalization of radiopeptides to rat C6 glioblastoma cells and rat brain homogenates from normal animals and a glioblastoma-induced model were assessed. Finally, ex vivo biodistribution studies were carried out. Radiochemical yields between 95–98% were reached for both peptides under optimized radiolabeling conditions. Both peptides were stable for up to 24 h in saline solution and in human serum. In addition, the radiopeptides have hydrophilic characteristics and a percentage of binding to serum proteins around 35% and 50% for the [131I]I-GRGDYV and [99mTc]Tc(CO)3-GRGDHV fragments, respectively. Radiopeptides showed the capacity of binding and internalization both in cell culture (C6) and rat brain homogenates. Biodistribution studies corroborated the results obtained with brain homogenates and confirmed the different binding characteristics due to the exchange of radionuclides and the presence of the tricarbonyl complex. Thereby, the results showed that both radiopeptides might be considered for future clinical applications. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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9 pages, 2083 KiB  
Article
Radioiodination and Purification of [131I]β-CIT and [131I]FP-CIT with an Automated Radiosynthesizer
by Elisabeth Plhak, Edith Gößnitzer, Reingard M. Aigner and Herbert Kvaternik
Pharmaceuticals 2022, 15(1), 96; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15010096 - 14 Jan 2022
Cited by 2 | Viewed by 1930
Abstract
Dopaminergic transporter (DAT) imaging with single photon emission computed tomography (SPECT) is used to diagnose Parkinson’s disease and to differentiate it from other neurodegenerative disorders without presynaptic dopaminergic dysfunction. The radioiodinated tropane alkaloids [123I]FP-CIT and [123I]β-CIT enable the evaluation [...] Read more.
Dopaminergic transporter (DAT) imaging with single photon emission computed tomography (SPECT) is used to diagnose Parkinson’s disease and to differentiate it from other neurodegenerative disorders without presynaptic dopaminergic dysfunction. The radioiodinated tropane alkaloids [123I]FP-CIT and [123I]β-CIT enable the evaluation of the integrity of DATs. Commonly, the labeling of these compounds is performed by electrophilic substitution of the alkylstannylated precursors with radioactive iodine and following purification by HPLC or solid phase extraction (SPE). This work presents the first radioiodination of β-CIT and FP-CIT with no carrier added [131I]NaI on a Scintomics GRP synthesis module. Free iodine-131 and impurities were removed by SPE over a C-18 Sep-Pak cartridge. We achieved a radiochemical yield of >75% and a radiochemical purity of >98% with both compounds. Our development of an automated synthesis on a commercially available synthesizer ensures robust and efficient labeling of [131I]FP-CIT and [131I]β-CIT starting with low concentrated radioiodine. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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13 pages, 2025 KiB  
Article
Covalent 18F-Radiotracers for SNAPTag: A New Toolbox for Reporter Gene Imaging
by Sophie Stotz, Gregory D. Bowden, Jonathan M. Cotton, Bernd J. Pichler and Andreas Maurer
Pharmaceuticals 2021, 14(9), 897; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090897 - 03 Sep 2021
Cited by 5 | Viewed by 2719
Abstract
There is a need for versatile in vivo nuclear imaging reporter systems to foster preclinical and clinical research. We explore the applicability of the SNAPTag and novel radiolabeled small-molecule ligands as a versatile reporter gene system for in vivo nuclear imaging. SNAPTag is [...] Read more.
There is a need for versatile in vivo nuclear imaging reporter systems to foster preclinical and clinical research. We explore the applicability of the SNAPTag and novel radiolabeled small-molecule ligands as a versatile reporter gene system for in vivo nuclear imaging. SNAPTag is a high-affinity protein tag used in a variety of biochemical research areas and based on the suicide DNA repair enzyme O6-methylguanine methyl transferase (MGMT). Its ligands are well suited for reporter gene imaging as the benzyl guanine core scaffold can be derivatized with fluorescent or radiolabeled moieties for various applications. Three guanine-based SNAPTag ligands ([18F]FBBG, [18F]pFBG and [18F]mFBG) were synthesized in high yields and were (radio)chemically characterized. HEK293 cells were engineered to express the SNAPTag on the cell surface and served as cell model to assess target affinity by radiotracer uptake assays, Western blotting and SDS-PAGE autoradiography. A subcutaneous HEK293-SNAPTag xenograft model in immunodeficient mice was used for in vivo evaluation of [18F]FBBG and [18F]pFBG while the biodistribution of [18F]mFBG was characterized in naïve animals. The results were validated by ex vivo biodistribution studies and immunofluorescence staining of the xenografts. All three radiotracers were produced in high radiochemical purity, molar activity and good yields. Western blot analysis revealed successful SNAPTag expression by the transfected HEK293 cells. In vitro testing revealed high target affinity of all three tracers with an up to 191-fold higher signal in the HEK293-SNAPTag cells compared to untransfected cells. This was further supported by a prominent radioactive protein band at the expected size in the SDS-PAGE autoradiograph of cells incubated with [18F]FBBG or [18F]pFBG. The in vivo studies demonstrated high uptake in HEK293-SNAP xenografts compared to HEK293 xenografts with excellent tumor-to-muscle ratios (7.5 ± 4.2 for [18F]FBBG and 10.6 ± 6.2 for [18F]pFBG). In contrast to [18F]pFBG and its chemical analogue [18F]mFBG, [18F]FBBG showed no signs of unspecific bone uptake and defluorination in vivo. Radiolabeled SNAPTag ligands bear great potential for clinical applications such as in vivo tracking of cell populations, antibody fragments and targeted radiotherapy. With excellent target affinity, good stability, and low non-specific binding, [18F]FBBG is a highly promising candidate for further preclinical evaluation. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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11 pages, 3084 KiB  
Article
18F-Fluorination Using Tri-Tert-Butanol Ammonium Iodide as Phase-Transfer Catalyst: An Alternative Minimalist Approach
by Sandip S. Shinde, Kim-Viktoria Bolik, Simone Maschauer and Olaf Prante
Pharmaceuticals 2021, 14(9), 833; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090833 - 24 Aug 2021
Cited by 5 | Viewed by 2363
Abstract
The 18F syntheses of tracers for positron emission tomography (PET) typically require several steps, including extraction of [18F]fluoride from H2[18O]O, elution, and drying, prior to nucleophilic substitution reaction, being a laborious and time-consuming process. The elution [...] Read more.
The 18F syntheses of tracers for positron emission tomography (PET) typically require several steps, including extraction of [18F]fluoride from H2[18O]O, elution, and drying, prior to nucleophilic substitution reaction, being a laborious and time-consuming process. The elution of [18F]fluoride is commonly achieved by phase transfer catalysts (PTC) in aqueous solution, which makes azeotropic drying indispensable. The ideal PTC is characterized by a slightly basic nature, its capacity to elute [18F]fluoride with anhydrous solvents, and its efficient complex formation with [18F]fluoride during subsequent labeling. Herein, we developed tri-(tert-butanol)-methylammonium iodide (TBMA-I), a quaternary ammonium salt serving as the PTC for 18F-fluorination reactions. The favorable elution efficiency of [18F]fluoride using TBMA-I was demonstrated with aprotic and protic solvents, maintaining high 18F-recoveries of 96–99%. 18F-labeling reactions using TBMA-I as PTC were studied with aliphatic 1,3-ditosylpropane and aryl pinacol boronate esters as precursors, providing 18F-labeled products in moderate-to-high radiochemical yields. TBMA-I revealed adequate properties for application to 18F-fluorination reactions and could be used for elution of [18F]fluoride with MeOH, omitting an additional base and azeotropic drying prior to 18F-labeling. We speculate that the tert-alcohol functionality of TBMA-I promotes intermolecular hydrogen bonding, which enhances the elution efficiency and stability of [18F]fluoride during nucleophilic 18F-fluorination. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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11 pages, 1623 KiB  
Article
Labelling via [Al18F]2+ Using Precomplexed Al-NODA Moieties
by Daniel Kang, Ulrich Simon, Felix M. Mottaghy and Andreas T. J. Vogg
Pharmaceuticals 2021, 14(8), 818; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14080818 - 20 Aug 2021
Cited by 4 | Viewed by 2331
Abstract
Over the past 20 years, 68Ga-labelled radiopharmaceuticals have become an important part in clinical routine. However, the worldwide supply with 68Ge/68Ga generators is limited as well as the number of patient doses per batch of 68Ga radiopharmaceutical. In [...] Read more.
Over the past 20 years, 68Ga-labelled radiopharmaceuticals have become an important part in clinical routine. However, the worldwide supply with 68Ge/68Ga generators is limited as well as the number of patient doses per batch of 68Ga radiopharmaceutical. In the recent years, a new technique appeared, making use of the ease of aqueous labelling via chelators as with 68Ga but using 18F instead. This technique takes advantage of the strong coordinative bond between aluminium and fluoride, realized in the aqueous cation [Al18F]2+. Most applications to date make use of one-pot syntheses with free Al(III) ions in the system. In contrast, we investigated the labelling approach split into two steps: generating the Al-bearing precursor in pure form and using this Al compound as a precursor in the labelling step with aqueous [18F]fluoride. Hence, no free Al3+ ions are present in the labelling step. We investigated the impact of parameters: temperature, pH, addition of organic solvent, and reaction time using the model chelator NH2-MPAA-NODA. With optimized parameters we could stably achieve a 80% radiochemical yield exerting a 30-min reaction time at 100 °C. This technique has the potential to become an important approach in radiopharmaceutical syntheses. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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12 pages, 1884 KiB  
Article
Synthesis and Biological Evaluation of a Radiolabeled PET (Positron Emission Tomography) Probe for Visualization of In Vivo α-Fucosidase Expression
by Jonathan Cotton, Chris Marc Goehring, Anna Kuehn, Andreas Maurer, Kerstin Fuchs and Bernd J. Pichler
Pharmaceuticals 2021, 14(8), 745; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14080745 - 29 Jul 2021
Viewed by 1866
Abstract
The acidic hydrolase α-fucosidase (AF) is a biomarker for maladies such as cancer and inflammation. The most advanced probes for α-fucosidase are unfortunately constrained to ex vivo or in vitro applications. The in vivo detection and quantification of AF using positron emission tomography [...] Read more.
The acidic hydrolase α-fucosidase (AF) is a biomarker for maladies such as cancer and inflammation. The most advanced probes for α-fucosidase are unfortunately constrained to ex vivo or in vitro applications. The in vivo detection and quantification of AF using positron emission tomography would allow for better discovery and diagnosis of disease as well as provide better understanding of disease progression. We synthesized, characterized, and evaluated a radiolabeled small molecule inhibitor of AF based on a known molecule. The radiosynthesis involved the 11C methylation of a phenoxide, which was generated in situ by ultrasonification of the precursor with sodium hydride. The tracer was produced with a decay corrected yield of 41.7 ± 16.5% and had a molar activity of 65.4 ± 30.3 GBq/μmol. The tracer was shown to be stable in mouse serum at 60 min. To test the new tracer, HCT116 colorectal carcinoma cells were engineered to overexpress human AF. In vitro evaluation revealed 3.5-fold higher uptake in HCT116AF cells compared to HCT116 controls (26.4 ± 7.8 vs. 7.5 ± 1.0 kBq/106 cells). Static PET scans 50 min post injection revealed 2.5-fold higher tracer uptake in the HCT116AF tumors (3.0 ± 0.8%ID/cc (n = 6)) compared with the controls (1.2 ± 0.8 (n = 5)). Dynamic scans showed higher uptake in the HCT116AF tumors at all time-points (n = 2). Ex vivo analysis of the tumors, utilizing fluorescent DDK2 antibodies, confirmed the expression of human AF in the HCT116AF xenografts. We have developed a novel PET tracer to image AF in vivo and will now apply this to relevant disease models. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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17 pages, 2452 KiB  
Article
GMP-Compliant Radiosynthesis of [18F]GP1, a Novel PET Tracer for the Detection of Thrombi
by Verena Hugenberg, Marion Zerna, Mathias Berndt, Reinhard Zabel, Rainer Preuss, Dirk Rolfsmeier, Janet Wegener, Henrik Fox, Astrid Kassner, Hendrik Milting, Norman Koglin, Andrew W. Stephens, Jan F. Gummert, Wolfgang Burchert and Marcus-André Deutsch
Pharmaceuticals 2021, 14(8), 739; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14080739 - 28 Jul 2021
Cited by 6 | Viewed by 2801
Abstract
Thrombus formation and thromboembolic events play important roles in various cardiovascular pathologies. The key receptor involved in platelet aggregation is the fibrinogen receptor glycoprotein IIb/IIIa. [18F]GP1, a derivative of the GPIIb/IIIa antagonist elarofiban, is a specific 18F-labeled small-molecule radiotracer that [...] Read more.
Thrombus formation and thromboembolic events play important roles in various cardiovascular pathologies. The key receptor involved in platelet aggregation is the fibrinogen receptor glycoprotein IIb/IIIa. [18F]GP1, a derivative of the GPIIb/IIIa antagonist elarofiban, is a specific 18F-labeled small-molecule radiotracer that binds with high affinity to GPIIb/IIIa receptors of activated platelets. An improved, robust and fully automated radiosynthesis of [18F]GP1 has been developed. [18F]GP1 has been synthesized with decay corrected radiochemical yields of 38 ± 6%, with a radiochemical concentration up to 1900 MBq/mL, molar activities of 952–9428 GBq/µmol and a radio-chemical purity >98%. After determination of the optimal reaction conditions, in particular for HPLC separation, adaption of the reaction conditions to PET center requirements, validation of the manufacturing process and the quality control methods, the synthesis of [18F]GP1 was successfully implemented to GMP standards and was available for clinical application. We describe the GMP-compliant synthesis of the novel radiotracer [18F]GP1. Moreover, we provide some proof-of-concept examples for clinical application in the cardiovascular field. PET/CT with the novel small-molecular radiotracer [18F]GP1 may serve as a novel highly sensitive tool for visualizing active platelet aggregation at the molecular level. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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10 pages, 936 KiB  
Article
Ac-EAZY! Towards GMP-Compliant Module Syntheses of 225Ac-Labeled Peptides for Clinical Application
by Marc Pretze, Falk Kunkel, Roswitha Runge, Robert Freudenberg, Anja Braune, Holger Hartmann, Uwe Schwarz, Claudia Brogsitter and Jörg Kotzerke
Pharmaceuticals 2021, 14(7), 652; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070652 - 06 Jul 2021
Cited by 10 | Viewed by 4035
Abstract
The application of 225Ac (half-life T1/2 = 9.92 d) dramatically reduces the activity used for peptide receptor radionuclide therapy by a factor of 1000 in comparison to 90Y, 177Lu or 188Re while maintaining the therapeutic outcome. Additionally, the [...] Read more.
The application of 225Ac (half-life T1/2 = 9.92 d) dramatically reduces the activity used for peptide receptor radionuclide therapy by a factor of 1000 in comparison to 90Y, 177Lu or 188Re while maintaining the therapeutic outcome. Additionally, the range of alpha particles of 225Ac and its daughter nuclides in tissue is much lower (47–85 μm for alpha energies Eα = 5.8–8.4 MeV), which results in a very precise dose deposition within the tumor. DOTA-conjugated commercially available peptides used for endoradiotherapy, which can readily be labeled with 177Lu or 90Y, can also accommodate 225Ac. The benefits are lower doses in normal tissue for the patient, dose reduction of the employees and environment and less shielding material. The low availability of 225Ac activity is preventing its application in clinical practice. Overcoming this barrier would open a broad field of 225Ac therapy. Independent which production pathway of 225Ac proves the most feasible, the use of automated synthesis and feasible and reproducible patient doses are needed. The Modular-Lab EAZY is one example of a GMP-compliant system, and the cassettes used for synthesis are small. Therefore, also the waste after the synthesis can be minimized. In this work, two different automated setups with different purification systems are presented. In its final configuration, three masterbatches were performed on the ML EAZY for DOTA-TATE and PSMA-I&T, respectively, fulfilling all quality criteria with final radiochemical yields of 80–90% for the 225Ac-labeled peptides. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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17 pages, 3243 KiB  
Article
Fully Automated GMP-Compliant Synthesis of [18F]FE-PE2I
by Klas Bratteby, Charlotte Lund Denholt, Szabolcs Lehel, Ida Nymann Petersen, Jacob Madsen, Maria Erlandsson, Tomas Ohlsson, Matthias Manfred Herth and Nic Gillings
Pharmaceuticals 2021, 14(7), 601; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070601 - 22 Jun 2021
Cited by 5 | Viewed by 2618
Abstract
In the struggle to understand and accurately diagnose Parkinson′s disease, radiopharmaceuticals and medical imaging techniques have played a major role. By being able to image and quantify the dopamine transporter density, noninvasive diagnostic imaging has become the gold standard. In the shift from [...] Read more.
In the struggle to understand and accurately diagnose Parkinson′s disease, radiopharmaceuticals and medical imaging techniques have played a major role. By being able to image and quantify the dopamine transporter density, noninvasive diagnostic imaging has become the gold standard. In the shift from the first generation of SPECT tracers, the fluorine-18-labeled tracer [18F]FE-PE2I has emerged as the agent of choice for many physicians. However, implementing suitable synthesis for the production of [18F]FE-PE2I has proved more challenging than expected. Through a thorough analysis of the relevant factors affecting the final radiochemical yield, we were able to implement high-yielding fully automated GMP-compliant synthesis of [18F]FE-PE2I on a Synthera®+ platform. By reaching RCYs up to 62%, it allowed us to isolate 25 GBq of the formulated product, and an optimized formulation resulted in the shelf life of 6 h, satisfying the increased demand for this radiopharmaceutical. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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17 pages, 1718 KiB  
Article
Radiopharmaceutical Formulation and Preclinical Testing of 68Ga-Labeled DOTA-MGS5 for the Regulatory Approval of a First Exploratory Clinical Trial
by Anton A. Hörmann, Maximilian Klingler, Christine Rangger, Christian Mair, Clemens Decristoforo, Christian Uprimny, Irene J. Virgolini and Elisabeth von Guggenberg
Pharmaceuticals 2021, 14(6), 575; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060575 - 16 Jun 2021
Cited by 8 | Viewed by 2784
Abstract
The new minigastrin analog DOTA-MGS5 is a promising new candidate for targeting cholecystokinin-2 receptor (CCK2R)-expressing tumors. To enable the clinical translation of PET/CT imaging using 68Ga-labeled DOTA-MGS5, different quality and safety aspects need to be considered to comply with the regulatory framework [...] Read more.
The new minigastrin analog DOTA-MGS5 is a promising new candidate for targeting cholecystokinin-2 receptor (CCK2R)-expressing tumors. To enable the clinical translation of PET/CT imaging using 68Ga-labeled DOTA-MGS5, different quality and safety aspects need to be considered to comply with the regulatory framework for clinical trial application. The preparation of the radiopharmaceutical was established using a cassette-based automated synthesis unit. Product specifications, including analytical procedures and acceptance criteria, were adopted from Ph. Eur. monographs for other 68Ga-labeled radiopharmaceuticals. Non-clinical studies included receptor affinity and cell uptake studies using two different CCK2R-expressing cell lines, as well as pharmacokinetic biodistribution studies in BALB/c mice for dosimetry calculations and toxicological studies in Wistar rats. The produced masterbatches fulfilled the defined acceptance criteria. DOTA-MGS5, with confirmed affinity to the CCK2R, showed a high specific cell uptake and no interaction with other receptors in vitro when radiolabeled with gallium-68. Favorable in vivo properties were observed in biodistribution and dosimetry studies. An effective dose of ~0.01 mSv/MBq was estimated for humans utilizing OLINDA/EXM software. A maximum peptide dose of 50 µg was established for the initial clinical dose based on the toxicity study in rats. The standardized production of [68Ga]Ga-DOTA-MGS5 using an automated synthesis module and the performed non-clinical safety studies support a first exploratory clinical trial with this new PET imaging agent. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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30 pages, 5415 KiB  
Article
Design, Synthesis, In Vitro and In Vivo Evaluation of Heterobivalent SiFAlin-Modified Peptidic Radioligands Targeting Both Integrin αvβ3 and the MC1 Receptor—Suitable for the Specific Visualization of Melanomas?
by Xia Cheng, Ralph Hübner, Valeska von Kiedrowski, Gert Fricker, Ralf Schirrmacher, Carmen Wängler and Björn Wängler
Pharmaceuticals 2021, 14(6), 547; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060547 - 07 Jun 2021
Cited by 7 | Viewed by 3335
Abstract
Combining two peptides addressing two different receptors to a heterobivalent peptidic ligand (HBPL) is thought to enable an improved tumor-targeting sensitivity and thus tumor visualization, compared to monovalent peptide ligands. In the case of melanoma, the Melanocortin-1 receptor (MC1R), which is stably overexpressed [...] Read more.
Combining two peptides addressing two different receptors to a heterobivalent peptidic ligand (HBPL) is thought to enable an improved tumor-targeting sensitivity and thus tumor visualization, compared to monovalent peptide ligands. In the case of melanoma, the Melanocortin-1 receptor (MC1R), which is stably overexpressed in the majority of primary malignant melanomas, and integrin αvβ3, which is involved in lymph node metastasis and therefore has an important role in the transition from local to metastatic disease, are important target receptors. Thus, if a radiolabeled HBPL could be developed that was able to bind to both receptor types, the early diagnosis and correct staging of the disease would be significantly increased. Here, we report on the design, synthesis, radiolabeling and in vitro and in vivo testing of different SiFAlin-modified HBPLs (SiFA = silicon fluoride acceptor), consisting of an MC1R-targeting (GG-Nle-c(DHfRWK)) and an integrin αvβ3-affine peptide (c(RGDfK)), being connected by a symmetrically branching framework including linkers of differing length and composition. Kit-like 18F-radiolabeling of the HBPLs 1–6 provided the labeled products [18F]1–[18F]6 in radiochemical yields of 27–50%, radiochemical purities of ≥95% and non-optimized molar activities of 17–51 GBq/μmol within short preparation times of 25 min. Besides the evaluation of radiotracers regarding logD(7.4) and stability in human serum, the receptor affinities of the HBPLs were investigated in vitro on cell lines overexpressing integrin αvβ3 (U87MG cells) or the MC1R (B16F10). Based on these results, the most promising compounds [18F]2, showing the highest affinity to both target receptors (IC50 (B16F10) = 0.99 ± 0.11 nM, IC50 (U87MG) = 1300 ± 288 nM), and [18F]4, exhibiting the highest hydrophilicity (logD(7.4) = −1.39 ± 0.03), were further investigated in vivo and ex vivo in a xenograft mouse model bearing both tumors. For both HBPLs, clear visualization of B16F10, as well as U87MG tumors, was feasible. Blocking studies using the respective monospecific peptides demonstrated both peptide binders of the HBPLs contributing to tumor uptake. Despite the somewhat lower target receptor affinities (IC50 (B16F10) = 6.00 ± 0.47 nM and IC50 (U87MG) = 2034 ± 323 nM) of [18F]4, the tracer showed higher absolute tumor uptakes ([18F]4: 2.58 ± 0.86% ID/g in B16F10 tumors and 3.92 ± 1.31% ID/g in U87MG tumors; [18F]2: 2.32 ± 0.49% ID/g in B16F10 tumors and 2.33 ± 0.46% ID/g in U87MG tumors) as well as higher tumor-to-background ratios than [18F]2. Thus, [18F]4 demonstrates to be a highly potent radiotracer for the sensitive and bispecific imaging of malignant melanoma by PET/CT imaging and impressively illustrates the suitability of the underlying concept to develop heterobivalent integrin αvβ3- and MC1R-bispecific radioligands for the sensitive and specific imaging of malignant melanoma by PET/CT. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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14 pages, 2501 KiB  
Article
Standardization of the [68Ga]Ga-PSMA-11 Radiolabeling Protocol in an Automatic Synthesis Module: Assessments for PET Imaging of Prostate Cancer
by Leonardo L. Fuscaldi, Danielle V. Sobral, Ana Claudia R. Durante, Fernanda F. Mendonça, Ana Cláudia C. Miranda, Marcelo L. da Cunha, Luciana Malavolta, Jorge Mejia and Marycel F. de Barboza
Pharmaceuticals 2021, 14(5), 385; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14050385 - 21 Apr 2021
Cited by 13 | Viewed by 3246
Abstract
Prostate-specific membrane antigen (PSMA) is a glycoprotein present in the prostate, that is overexpressed in prostate cancer (PCa). Recently, PSMA-directed radiopharmaceuticals have been developed, allowing the pinpointing of tumors with the Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) imaging [...] Read more.
Prostate-specific membrane antigen (PSMA) is a glycoprotein present in the prostate, that is overexpressed in prostate cancer (PCa). Recently, PSMA-directed radiopharmaceuticals have been developed, allowing the pinpointing of tumors with the Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) imaging techniques. The aim of the present work was to standardize and validate an automatic synthesis module-based radiolabeling protocol for [68Ga]Ga-PSMA-11, as well as to produce a radiopharmaceutical for PET imaging of PCa malignancies. [68Ga]Ga-PSMA-11 was evaluated to determine the radiochemical purity (RCP), stability in saline solution and serum, lipophilicity, affinity to serum proteins, binding and internalization to lymph node carcinoma of the prostate (LNCaP) cells, and ex vivo biodistribution in mice. The radiopharmaceutical was produced with an RCP of 99.06 ± 0.10%, which was assessed with reversed-phase high-performance liquid chromatography (RP-HPLC). The product was stable in saline solution for up to 4 h (RCP > 98%) and in serum for up to 1 h (RCP > 95%). The lipophilicity was determined as −3.80 ± 0.15, while the serum protein binding (SPB) was <17%. The percentages of binding to LNCaP cells were 4.07 ± 0.51% (30 min) and 4.56 ± 0.46% (60 min), while 19.22 ± 2.73% (30 min) and 16.85 ± 1.34% (60 min) of bound material was internalized. High accumulation of [68Ga]Ga-PSMA-11 was observed in the kidneys, spleen, and tumor, with a tumor-to-contralateral-muscle ratio of >8.5 and a tumor-to-blood ratio of >3.5. In conclusion, an automatic synthesis module-based radiolabeling protocol for [68Ga]Ga-PSMA-11 was standardized and the product was evaluated, thus verifying its characteristics for PET imaging of PCa tumors in a clinical environment. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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17 pages, 4312 KiB  
Article
Feasibility of Developing Radiotracers for MDM2: Synthesis and Preliminary Evaluation of an 18F-Labeled Analogue of the MDM2 Inhibitor SP-141
by Satish K. Chitneni, Zhengyuan Zhou, Brian E. Watts and Michael R. Zalutsky
Pharmaceuticals 2021, 14(4), 358; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14040358 - 13 Apr 2021
Cited by 2 | Viewed by 2053
Abstract
Murine double minute 2 (MDM2), a negative regulator of the p53 tumor suppressor protein, is overexpressed in several human cancers. Herein we investigate the feasibility of developing 18F-labeled compounds based on the small molecule inhibitor SP-141 for imaging tumor MDM2 expression levels [...] Read more.
Murine double minute 2 (MDM2), a negative regulator of the p53 tumor suppressor protein, is overexpressed in several human cancers. Herein we investigate the feasibility of developing 18F-labeled compounds based on the small molecule inhibitor SP-141 for imaging tumor MDM2 expression levels with positron emission tomography (PET). Three nonradioactive fluorinated SP-141 analogues, 1–3, were synthesized, and their binding to the MDM2 protein was analyzed by surface plasmon resonance (SPR). One of these, a fluoroethoxy analogue, was labeled with fluorine-18 (18F) using 18F-fluorethyl bromide to provide [18F]1 and evaluated in vitro and in vivo. SPR analysis confirmed the binding of the fluorinated analogues to MDM2 at 1.25–20 µM concentrations. Cell uptake studies revealed high uptake (67.5–71.4%/mg protein) and specificity of [18F]1 in MCF7 and HepG2 cells. The uptake of [18F]1 in these cells could be modulated using 100 µM SP-141, potentially reflecting changes in MDM2 expression because of p53 activation by SP-141. [18F]1 exhibited stable uptake and retention in HepG2 tumor xenografts (~3 %ID/g) in vivo, but poor clearance from blood and other normal tissues, yielding low tumor-to-background ratios (<2) at 2 h post injection. Our results suggest that [18F]1 has suboptimal characteristics for in vivo evaluation as a PET tracer for MDM2, but warrant radiolabeling and assessment of the other fluorinated analogues synthesized in this work, 2 and 3, and potentially other molecular scaffolds for developing MDM2 targeted radiotracers. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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16 pages, 5449 KiB  
Article
SPECT Imaging of SST2-Expressing Tumors with 99mTc-Based Somatostatin Receptor Antagonists: The Role of Tetraamine, HYNIC, and Spacers
by Raghuvir Haridas Gaonkar, Fabius Wiesmann, Luigi Del Pozzo, Lisa McDougall, Sandra Zanger, Renata Mikołajczak, Rosalba Mansi and Melpomeni Fani
Pharmaceuticals 2021, 14(4), 300; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14040300 - 28 Mar 2021
Cited by 6 | Viewed by 2220
Abstract
[99mTc]Tc-HYNIC-TOC is the most widely used 99mTc-labeled somatostatin receptor (SST) agonist for the SPECT imaging of SST-expressing tumors, such as neuroendocrine tumors. Recently, radiolabeled SST antagonists have shown improved diagnostic efficacy over agonists. 99mTc-labeled SST antagonists are lacking in [...] Read more.
[99mTc]Tc-HYNIC-TOC is the most widely used 99mTc-labeled somatostatin receptor (SST) agonist for the SPECT imaging of SST-expressing tumors, such as neuroendocrine tumors. Recently, radiolabeled SST antagonists have shown improved diagnostic efficacy over agonists. 99mTc-labeled SST antagonists are lacking in clinical practice. Surprisingly, when [99mTc]Tc-HYNIC was conjugated to the SST2 antagonist SS01, SST2 imaging was not feasible. This was not the case when [99mTc]Tc-N4 was conjugated to SS01. Here, we assessed the introduction of different spacers (X: β-Ala, Ahx, Aun and PEG4) among HYNIC and SS01 with the aim of restoring the affinity of HYNIC conjugates. In addition, we used the alternative antagonist JR11 for determining the suitability of HYNIC with 99mTc-labeled SST2 antagonists. We performed a head-to-head comparison of the N4 conjugates of SS01 and JR11. [99mTc]Tc-HYNIC-TOC was used as a reference, and HEK-SST2 cells were used for in vitro and in vivo evaluation. EDDA was used as a co-ligand for all [99mTc]Tc-HYNIC conjugates. The introduction of Ahx restored, to a great extent, the SST2-mediated cellular uptake of the [99mTc]Tc-HYNIC-X conjugates (X: spacer), albeit lower than the corresponding [99mTc]Tc-N4-conjugates. SPECT/CT images showed that all 99mTc-labeled conjugates accumulated in the tumor and kidneys with [99mTc]Tc-HYNIC-PEG4-SS01, [99mTc]Tc-N4-SS01 and [99mTc]Tc-N4-JR11 having notably higher kidney uptake. Biodistribution studies showed similar or better tumor-to-non-tumor ratios for the [99mTc]Tc-HYNIC-Ahx conjugates, compared to the [99mTc]Tc-N4 counterparts. The [99mTc]Tc-HYNIC-Ahx conjugates of SS01 and JR11 were comparable to [99mTc]Tc-HYNIC-TOC as imaging agents. HYNIC is a suitable chelator for the development of 99mTc-labeled SST2 antagonists when a spacer of appropriate length, such as Ahx, is used. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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21 pages, 2153 KiB  
Article
Development and Validation of a GMP-Compliant High-Pressure Liquid Chromatography Method for the Determination of the Chemical and Radiochemical Purity of [18F]PSMA-1007, a PET Tracer for the Imaging of Prostate Cancer
by Ines Katzschmann, Heike Marx, Klaus Kopka and Ute Hennrich
Pharmaceuticals 2021, 14(3), 188; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14030188 - 25 Feb 2021
Cited by 5 | Viewed by 2742
Abstract
For the PET imaging of prostate cancer, radiotracers targeting the prostate-specific membrane antigen (PSMA) are nowadays used in clinical practice. [18F]PSMA-1007, a radiopharmaceutical labeled with fluorine-18, has excellent properties for the detection of prostate cancer. Essential for the human use of [...] Read more.
For the PET imaging of prostate cancer, radiotracers targeting the prostate-specific membrane antigen (PSMA) are nowadays used in clinical practice. [18F]PSMA-1007, a radiopharmaceutical labeled with fluorine-18, has excellent properties for the detection of prostate cancer. Essential for the human use of a radiotracer is its production and quality control under GMP-compliance. For this purpose, all analytical methods have to be validated. [18F]PSMA-1007 is easily radiosynthesized in a one-step procedure and isolated using solid phase extraction (SPE) cartridges followed by formulation of a buffered injection solution and for the determination of its chemical and radiochemical purity a robust, fast and reliable quality control method using radio-HPLC is necessary. After development and optimizations overcoming problems in reproducibility, the here described radio-HPLC method fulfills all acceptance criteria—for e.g., specificity, linearity, and accuracy—and is therefore well suited for the routine quality control of [18F]PSMA-1007 before release of the radiopharmaceutical. Recently a European Pharmacopeia monograph for [18F]PSMA-1007 was published suggesting a different radio-HPLC method for the determination of its chemical and radiochemical purity. Since the here described method has certain advantages, not least of all easier technical implementation, it can be an attractive alternative to the monograph method. The here described method was successfully validated on several radio-HPLC systems in our lab and used for the analysis of more than 60 batches of [18F]PSMA-1007. Using this method, the chemical and radiochemical purity of [18F]PSMA-1007 can routinely be evaluated assuring patient safety. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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15 pages, 2680 KiB  
Article
Selection of the First 99mTc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation—Preclinical Assessment of Two Optimized Candidates
by Melpomeni Fani, Viktoria Weingaertner, Petra Kolenc Peitl, Rosalba Mansi, Raghuvir H. Gaonkar, Piotr Garnuszek, Renata Mikolajczak, Doroteja Novak, Urban Simoncic, Alicja Hubalewska-Dydejczyk, Christine Rangger, Piriya Kaeopookum and Clemens Decristoforo
Pharmaceuticals 2021, 14(1), 19; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010019 - 28 Dec 2020
Cited by 9 | Viewed by 2752
Abstract
Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project “TECANT” two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical [...] Read more.
Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project “TECANT” two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [99mTc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [99mTc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [99mTc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [99mTc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [99mTc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [99mTc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [99mTc]Tc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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Review

Jump to: Research

35 pages, 6667 KiB  
Review
The Development of Positron Emission Tomography Tracers for In Vivo Targeting the Kinase Domain of the Epidermal Growth Factor Receptor
by Antonia Högnäsbacka, Alex J. Poot, Danielle J. Vugts, Guus A. M. S. van Dongen and Albert D. Windhorst
Pharmaceuticals 2022, 15(4), 450; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15040450 - 05 Apr 2022
Cited by 7 | Viewed by 2467
Abstract
Multiple small molecule PET tracers have been developed for the imaging of the epidermal growth factor receptor (EGFR). These tracers target the tyrosine kinase (TK) domain of the receptor and have been used for both quantifying EGFR expression and to differentiate between EGFR [...] Read more.
Multiple small molecule PET tracers have been developed for the imaging of the epidermal growth factor receptor (EGFR). These tracers target the tyrosine kinase (TK) domain of the receptor and have been used for both quantifying EGFR expression and to differentiate between EGFR mutational statuses. However, the approaches for in vivo evaluation of these tracers are diverse and have resulted in data that are hard to compare. In this review, we analyze the historical development of the in vivo evaluation approaches, starting from the first EGFR TK PET tracer [11C]PD153035 to tracers developed based on TK inhibitors used for the clinical treatment of mutated EGFR expressing non-small cell lung cancer like [11C]erlotinib and [18F]afatinib. The evaluation of each tracer has been compiled to allow for a comparison between studies and ultimately between tracers. The main challenges for each group of tracers are thereafter discussed. Finally, this review addresses the challenges that need to be overcome to be able to efficiently drive EGFR PET imaging forward. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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13 pages, 1053 KiB  
Review
Experimental Nuclear Medicine Meets Tumor Biology
by Theresa Balber, Loan Tran, Katarína Benčurová, Julia Raitanen, Gerda Egger and Markus Mitterhauser
Pharmaceuticals 2022, 15(2), 227; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15020227 - 14 Feb 2022
Cited by 4 | Viewed by 1920
Abstract
Personalized treatment of cancer patients demands specific and validated biomarkers for tumor diagnosis and therapy. The development and validation of such require translational preclinical models that recapitulate human diseases as accurately as possible. Moreover, there is a need for convergence of different (pre)clinical [...] Read more.
Personalized treatment of cancer patients demands specific and validated biomarkers for tumor diagnosis and therapy. The development and validation of such require translational preclinical models that recapitulate human diseases as accurately as possible. Moreover, there is a need for convergence of different (pre)clinical disciplines that openly share their knowledge and methodologies. This review sheds light on the differential perception of biomarkers and gives an overview of currently used models in tracer development and approaches for biomarker discovery. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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22 pages, 4487 KiB  
Review
Sweetening Pharmaceutical Radiochemistry by 18F-Fluoroglycosylation: Recent Progress and Future Prospects
by Sandip S. Shinde, Simone Maschauer and Olaf Prante
Pharmaceuticals 2021, 14(11), 1175; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14111175 - 17 Nov 2021
Cited by 13 | Viewed by 2306
Abstract
In the field of 18F-chemistry for the development of radiopharmaceuticals for positron emission tomography (PET), various labeling strategies by the use of prosthetic groups have been implemented, including chemoselective 18F-labeling of biomolecules. Among those, chemoselective 18F-fluoroglycosylation methods focus on the [...] Read more.
In the field of 18F-chemistry for the development of radiopharmaceuticals for positron emission tomography (PET), various labeling strategies by the use of prosthetic groups have been implemented, including chemoselective 18F-labeling of biomolecules. Among those, chemoselective 18F-fluoroglycosylation methods focus on the sweetening of pharmaceutical radiochemistry by offering a highly valuable tool for the synthesis of 18F-glycoconjugates with suitable in vivo properties for PET imaging studies. A previous review covered the various 18F-fluoroglycosylation methods that were developed and applied as of 2014 (Maschauer and Prante, BioMed. Res. Int. 2014, 214748). This paper is an updated review, providing the recent progress in 18F-fluoroglycosylation reactions and the preclinical application of 18F-glycoconjugates, including small molecules, peptides, and high-molecular-weight proteins. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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12 pages, 3410 KiB  
Review
[68Ga]Ga-PSMA-11: The First FDA-Approved 68Ga-Radiopharmaceutical for PET Imaging of Prostate Cancer
by Ute Hennrich and Matthias Eder
Pharmaceuticals 2021, 14(8), 713; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14080713 - 23 Jul 2021
Cited by 56 | Viewed by 7320
Abstract
For the positron emission tomography (PET) imaging of prostate cancer, radiotracers targeting the prostate-specific membrane antigen (PSMA) are nowadays used in clinical practice. Almost 10 years after its discovery, [68Ga]Ga-PSMA-11 has been approved in the United States by the Food and [...] Read more.
For the positron emission tomography (PET) imaging of prostate cancer, radiotracers targeting the prostate-specific membrane antigen (PSMA) are nowadays used in clinical practice. Almost 10 years after its discovery, [68Ga]Ga-PSMA-11 has been approved in the United States by the Food and Drug Administration (FDA) as the first 68Ga-radiopharmaceutical for the PET imaging of PSMA-positive prostate cancer in 2020. This radiopharmaceutical combines the peptidomimetic Glu-NH-CO-NH-Lys(Ahx)-HBED-CC with the radionuclide 68Ga, enabling specific imaging of tumor cells expressing PSMA. Such a targeting approach may also be used for therapy planning as well as potentially for the evaluation of treatment response. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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19 pages, 2540 KiB  
Review
Recent Advances in the Clinical Translation of Silicon Fluoride Acceptor (SiFA) 18F-Radiopharmaceuticals
by Lexi Gower-Fry, Travis Kronemann, Andreas Dorian, Yinglan Pu, Carolin Jaworski, Carmen Wängler, Peter Bartenstein, Leonie Beyer, Simon Lindner, Klaus Jurkschat, Björn Wängler, Justin J. Bailey and Ralf Schirrmacher
Pharmaceuticals 2021, 14(7), 701; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070701 - 20 Jul 2021
Cited by 12 | Viewed by 3893
Abstract
The incorporation of silicon fluoride acceptor (SiFA) moieties into a variety of molecules, such as peptides, proteins and biologically relevant small molecules, has improved the generation of 18F-radiopharmaceuticals for medical imaging. The efficient isotopic exchange radiofluorination process, in combination with the enhanced [...] Read more.
The incorporation of silicon fluoride acceptor (SiFA) moieties into a variety of molecules, such as peptides, proteins and biologically relevant small molecules, has improved the generation of 18F-radiopharmaceuticals for medical imaging. The efficient isotopic exchange radiofluorination process, in combination with the enhanced [18F]SiFA in vivo stability, make it a suitable strategy for fluorine-18 incorporation. This review will highlight the clinical applicability of [18F]SiFA-labeled compounds and discuss the significant radiotracers currently in clinical use. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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50 pages, 10628 KiB  
Review
Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma
by Julie Bolcaen, Shankari Nair, Cathryn H. S. Driver, Tebatso M. G. Boshomane, Thomas Ebenhan and Charlot Vandevoorde
Pharmaceuticals 2021, 14(7), 626; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070626 - 29 Jun 2021
Cited by 12 | Viewed by 5294
Abstract
Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact [...] Read more.
Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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Graphical abstract

19 pages, 1307 KiB  
Review
Update on PET Tracer Development for Muscarinic Acetylcholine Receptors
by Marius Ozenil, Jonas Aronow, Marlon Millard, Thierry Langer, Wolfgang Wadsak, Marcus Hacker and Verena Pichler
Pharmaceuticals 2021, 14(6), 530; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060530 - 02 Jun 2021
Cited by 12 | Viewed by 3324
Abstract
The muscarinic cholinergic system regulates peripheral and central nervous system functions, and, thus, their potential as a therapeutic target for several neurodegenerative diseases is undoubted. A clinically applicable positron emission tomography (PET) tracer would facilitate the monitoring of disease progression, elucidate the role [...] Read more.
The muscarinic cholinergic system regulates peripheral and central nervous system functions, and, thus, their potential as a therapeutic target for several neurodegenerative diseases is undoubted. A clinically applicable positron emission tomography (PET) tracer would facilitate the monitoring of disease progression, elucidate the role of muscarinic acetylcholine receptors (mAChR) in disease development and would aid to clarify the diverse natural functions of mAChR regulation throughout the nervous system, which still are largely unresolved. Still, no mAChR PET tracer has yet found broad clinical application, which demands mAChR tracers with improved imaging properties. This paper reviews strategies of mAChR PET tracer design and summarizes the binding properties and preclinical evaluation of recent mAChR tracer candidates. Furthermore, this work identifies the current major challenges in mAChR PET tracer development and provides a perspective on future developments in this area of research. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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Graphical abstract

12 pages, 1330 KiB  
Review
Tauvid™: The First FDA-Approved PET Tracer for Imaging Tau Pathology in Alzheimer’s Disease
by Caitlin V. M. L. Jie, Valerie Treyer, Roger Schibli and Linjing Mu
Pharmaceuticals 2021, 14(2), 110; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14020110 - 30 Jan 2021
Cited by 47 | Viewed by 8467
Abstract
Tauvid has been approved by the U.S. Food and Drug Administration (FDA) in 2020 for positron emission tomography (PET) imaging of adult patients with cognitive impairments undergoing evaluation for Alzheimer’s disease (AD) based on tau pathology. Abnormal aggregation of tau proteins is one [...] Read more.
Tauvid has been approved by the U.S. Food and Drug Administration (FDA) in 2020 for positron emission tomography (PET) imaging of adult patients with cognitive impairments undergoing evaluation for Alzheimer’s disease (AD) based on tau pathology. Abnormal aggregation of tau proteins is one of the main pathologies present in AD and is receiving increasing attention as a diagnostic and therapeutic target. In this review, we summarised the production and quality control of Tauvid, its clinical application, pharmacology and pharmacokinetics, as well as its limitation due to off-target binding. Moreover, a brief overview on the second-generation of Tau PET tracers is provided. The approval of Tauvid marks a step forward in the field of AD research and opens up opportunities for second-generation tau tracers to advance tau PET imaging in the clinic. Full article
(This article belongs to the Special Issue Targets, Tracers and Translation, Part 2 - New Horizons in Radiopharmaceutical Development)
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