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Challenges in the Development of PET and SPECT Radiotracers: Innovative...
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Challenges in the Development of PET and SPECT Radiotracers: Innovative Ideas with Negative Outcomes

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

Deadline for manuscript submissions: 25 September 2025 | Viewed by 1475

Special Issue Editors

Dr. Magali Toussaint

E-Mail Website
Guest Editor
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site, Leipzig, Germany
Interests: brain tumours; PET/MRI; small animal imaging; radiotracer development
Dr. Barbara Wenzel

E-Mail Website
Guest Editor
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site, Leipzig, Germany
Interests: radiotracer development; brain PET imaging; radiochemistry; Fluorine-18; HPLC

Special Issue Information

Dear Colleagues,

We are pleased to announce a Special Issue dedicated to the challenges and innovative efforts in the development of PET and SPECT radiotracers. This collection aims to highlight the complexities and hurdles in this field and the importance of "unsuccessful" endeavors for the advancement of radiopharmaceutical research.

With this Special Issue, we will provide a space to present substantial research with negative results in the field of radiotracer development and seek to emphasize innovative ideas that, despite their potential, have resulted in supposedly unpublishable outcomes. We believe that knowing what fails is as important as knowing what succeeds to support a comprehensive understanding, encourage methodological improvements and finally strengthen the scientific community.

Radiotracer development for PET and SPECT imaging involves numerous challenges in medicinal chemistry, radiolabeling, purification, stability, target selectivity, and in vivo pharmacokinetics. These obstacles can lead to unexpected negative results, which are often underreported but crucial for scientific progress and innovation.

Publishing such results is essential for advancing our collective knowledge and guiding future research. Moreover, it prevents duplications of efforts and contributes to a more reliable scientific literature. We therefore look forward to receiving your contributions in the fields of medicinal chemistry, radiochemistry, and in vitro and/or in vivo preclinical evaluation of newly developed or known PET and SPECT radiopharmaceuticals.

This Special Issue is open to original research articles, brief reports, and reviews.

Dr. Magali Toussaint
Dr. Barbara Wenzel
Guest Editors

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

  • radiotracer development
  • positron emission tomography (PET)
  • single-photon emission computed tomography (SPECT)
  • negative results
  • diagnostic radiotracers
  • therapeutic radiopharmaceuticals
  • radiolabeling
  • automated synthesis and GMP
  • pre-clinical studies
  • medicinal chemistry

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Published Papers (2 papers)

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Research

25 pages, 4259 KiB  
Article
Towards Dual-Tracer SPECT for Prostate Cancer Imaging Using [99mTc]Tc-PSMA-I&S and [111In]In-RM2
by Carolina Giammei, Theresa Balber, Veronika Felber, Thomas Dillinger, Jens Cardinale, Marie R. Brandt, Anna Stingeder, Markus Mitterhauser, Gerda Egger and Thomas L. Mindt
Pharmaceuticals 2025, 18(7), 1002; https://doi.org/10.3390/ph18071002 - 3 Jul 2025
Viewed by 258
Abstract
Background/Objectives: Radiolabeled biomolecules specifically targeting overexpressed structures on tumor cells hold great potential for prostate cancer (PCa) imaging and therapy. Due to heterogeneous target expression, single radiopharmaceuticals may not detect or treat all lesions, while simultaneously applying two or more radiotracers potentially [...] Read more.
Background/Objectives: Radiolabeled biomolecules specifically targeting overexpressed structures on tumor cells hold great potential for prostate cancer (PCa) imaging and therapy. Due to heterogeneous target expression, single radiopharmaceuticals may not detect or treat all lesions, while simultaneously applying two or more radiotracers potentially improves staging, stratification, and therapy of cancer patients. This study explores a dual-tracer SPECT approach using [111In]In-RM2 (targeting the gastrin-releasing peptide receptor, GRPR) and [99mTc]Tc-PSMA-I&S (targeting the prostate-specific membrane antigen, PSMA) as a proof of concept. To mimic heterogeneous tumor lesions in the same individual, we aimed to establish a dual xenograft mouse model for preclinical evaluation. Methods: CHO-K1 cells underwent lentiviral transduction for human GRPR or human PSMA overexpression. Six-to-eight-week-old female immunodeficient mice (NOD SCID) were subsequently inoculated with transduced CHO-K1 cells in both flanks, enabling a dual xenograft with similar target density and growth of both xenografts. Respective dual-isotope imaging and γ-counting protocols were established. Target expression was analyzed ex vivo by Western blotting. Results: In vitro studies showed similar target-specific binding and internalization of [111In]In-RM2 and [99mTc]Tc-PSMA-I&S in transduced CHO-K1 cells compared to reference lines PC-3 and LNCaP. However, in vivo imaging showed negligible tumor uptake in xenografts of the transduced cell lines. Ex vivo analysis indicated a loss of the respective biomarkers in the xenografts. Conclusions: Although the technical feasibility of a dual-tracer SPECT imaging approach using 111In and 99mTc has been demonstrated, the potential of [99mTc]Tc-PSMA-I&S and [111In]In-RM2 in a dual-tracer cocktail to improve PCa diagnosis could not be verified. The animal model, and in particular the transduced cell lines developed exclusively for this project, proved to be unsuitable for this purpose. The in/ex vivo experiments indicated that results from an in vitro model may not necessarily be successfully transferred to an in vivo setting. To assess the potential of this dual-tracer concept to improve PCa diagnosis, optimized in vivo models are needed. Nevertheless, our strategies address key challenges in dual-tracer applications, aiming to optimize future SPECT imaging approaches. Full article
(This article belongs to the Special Issue Challenges in the Development of PET and SPECT Radiotracers: Innovative Ideas with Negative Outcomes)
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14 pages, 3879 KiB  
Article
PET Imaging Expedites Detection of Aberration in the Humanization of an Annexin A1 Targeting Antibody
by Hailey A. Houson, Brian D. Wright, Solana R. Fernandez, Tim Buss, Sharon L. White, Brittany Cederstrom, James M. Omweri, Jonathan E. McConathy, Jan E. Schnitzer and Suzanne E. Lapi
Pharmaceuticals 2025, 18(3), 295; https://doi.org/10.3390/ph18030295 - 21 Feb 2025
Viewed by 618
Abstract
Objectives: Annexin-A1 is a 37 kDa phospholipid-binding protein which is concentrated in a truncated 34 kDa form (AnnA1) in caveolae on the tumor vascular endothelial cell surface with expression in many tumor types. PRISM developed the monoclonal mouse antibody mAnnA1 against AnnA1 [...] Read more.
Objectives: Annexin-A1 is a 37 kDa phospholipid-binding protein which is concentrated in a truncated 34 kDa form (AnnA1) in caveolae on the tumor vascular endothelial cell surface with expression in many tumor types. PRISM developed the monoclonal mouse antibody mAnnA1 against AnnA1 for evaluation of AnnA1 as a potential target for imaging and therapy in oncology. mAnnA1 was humanized to make hAnnA1 for translation to clinical studies. Both PRISM-produced mAnnA1 and cGMP contractor-produced hAnnA1 were investigated using noninvasive PET/CT imaging, and dosimetry was evaluated to enable clinical translation of this strategy and to investigate in vivo behavior of hAnnA1. Methods: Antibodies mAnnA1 and hAnnA1 (PRISM “hAnnA1-P” or contractor generated “hAnnA1-C”) were conjugated with the chelator deferoxamine and evaluated for immunoreactivity with ELISA. Conjugated antibodies were radiolabeled with zirconium-89. Naïve mice, rats, and non-human primates (NHP) were injected with [89Zr]mAnnA1 or [89Zr]hAnnA1 and imaged with PET/CT up to 10 days post injection. After imaging, mice and rats were euthanized and organs were collected, weighed, and radioactivity was quantified using a gamma counter. Dosimetry in mice and NHPs were calculated using OLINDA. Results: [89Zr]mAnnA1 showed similar biodistribution to other antibodies with slow clearance through the liver. Transition to [89Zr]hAnnA1-C during the dosimetry studies revealed substantial uptake in the spleen (130 ± 48% ID/g at day 5 post injection in female BALB/c), which was not observed with [89Zr]mAnnA1 (5.6 ± 1.7% ID/g at day 7 PI). Further studies in multiple strains of mice showed variable elevated splenic uptake of [89Zr]hAnnA1-C across mouse strains, with the highest uptake observed in female BALB/c mice (118.4 ± 23.1% ID/g) and the lowest uptake observed in male CD1 mice (34.7 ± 10.2% ID/g). Additionally, splenic uptake of hAnnA1-C was observed in Fischer rats (2.8 ± 0.6% ID/organ) and NHPs (1.6 ± 0.6% ID/organ), although at lower levels than what was observed in BALB/c mice (8.8 ± 1.8% ID/organ). Dosimetry results showed similar values between estimates based on mouse and NHP data, with the largest difference seen in the spleen (5.2 vs. 2.6 mSv/MBq in females respectively). Sequencing of hAnnA1-C revealed a frameshift mutation in the antibody sequence introduced during cGMP manufacture. Restoration of the antibody sequence by PRISM returned the antibody distribution into alignment with mAnnA1. Conclusions: An aberration introduced during cGMP production of hAnnA1-C resulted in increased splenic uptake and alteration of the biodistribution in mice. PET imaging enabled quantitative detection of the immunogenic behavior of hAnnA1, which led to detection of the sequence error. Restoration of the sequence resulted in an antibody which was non-immunogenic to mice. Full article
(This article belongs to the Special Issue Challenges in the Development of PET and SPECT Radiotracers: Innovative Ideas with Negative Outcomes)
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