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Pharmaceuticals
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Advances in Theranostic Radiopharmaceuticals
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Advances in Theranostic Radiopharmaceuticals

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

Deadline for manuscript submissions: 31 December 2026 | Viewed by 4945

Editor

Dr. Janke Kleynhans

E-Mail Website
Guest Editor
Department of Nuclear Chemistry, Faculty of Nuclear Sciences and Physical Engineering, Czech Technical University in Prague, Prague, Czech Republic
Interests: radiochemistry; radiopharmacy; generator-based radionuclides; preclinical imaging; radioanalytical procedures

Special Issue Information

Dear Colleagues,

Over the past decade, the field of theranostic radiopharmaceuticals has rapidly expanded to take centre stage in the field of precision medicine. This paradigm has been proven successful and is currently being expanded beyond traditional targets to include new mechanisms, radionuclides, and delivery systems that are being applied in the field of Nuclear Medicine for the first time.

Recent advances in radiochemistry, isotope production, and biology have enabled the translation of increasingly sophisticated radiopharmaceuticals from bench to bedside. The field of targeted alpha therapy has shown substantial growth. Established beta-minus emitters such as lutetium-177 and yttrium-90 have steadily increased, and newer dual-mechanism radionuclides such as lead-212 and terbium-161 are the newer options in the therapeutic toolbox. These novel therapies go hand-in-hand with advances on the diagnostic side, with implementation of staple radionuclides such as technetium-99m, gallium-68, and fluorine-18, but also some more exotic options being investigated. At the same time, quantitative imaging, dosimetry, and radiobiology-based modelling are refining our understanding of therapeutic efficacy and safety.

This Special Issue of Pharmaceuticals invites original research papers and comprehensive reviews that highlight innovation in the field of radiotheranostics as well as ongoing challenges. Topics of interest include (but are not limited to) novel radionuclide production methods, advances in radiolabelling methods, new target discovery, and novel radiopharmaceutical development, including in vivo evaluations, clinical translation of novel diagnostic or theranostic radiopharmaceuticals, and investigations of the radiobiology governing theranostic applications. The hope is that this issue will contain contributions that showcase the state-of-the-art and inspire and inform the next generation of radiopharmaceutical innovation.

Dr. Janke Kleynhans
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 250 words) can be sent to the Editorial Office for assessment.

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-anonymized 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

  • theranostics
  • radiopharmacy
  • targeted alpha therapy
  • preclinical imaging
  • radiobiology
  • radioisotope production
  • molecular radiotherapy
  • positron emission tomography
  • single photon emission tomography

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Published Papers (4 papers)

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Research

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16 pages, 1219 KB  
Article
Selective CXCR4-Targeting Radioconjugates Derived from LY2510924: Evaluation of [18F]AlF-NOTA-SC, [177Lu]Lu-BL02, and [161Tb]Tb-BL02 for Theranostic Development
by Muriel Aline Spahn, Tom Van Loy, Christophe M. Deroose, Sofie Celen, Dominique Schols, Guy Bormans, Janke Kleynhans and Frederik Cleeren
Pharmaceuticals 2026, 19(8), 1160; https://doi.org/10.3390/ph19081160 - 25 Jul 2026
Viewed by 355
Abstract
Background/Objectives: The chemokine receptor CXCR4 plays a pivotal role in tumor progression, metastasis, and therapy resistance and is frequently overexpressed in hematologic malignancies, including multiple myeloma and lymphoma. This study investigates a CXCR4-targeted theranostic platform comprising a PET imaging agent and two [...] Read more.
Background/Objectives: The chemokine receptor CXCR4 plays a pivotal role in tumor progression, metastasis, and therapy resistance and is frequently overexpressed in hematologic malignancies, including multiple myeloma and lymphoma. This study investigates a CXCR4-targeted theranostic platform comprising a PET imaging agent and two therapeutic radioconjugates derived from the high-affinity CXCR4 antagonist LY2510924. Methods: The PET tracer [18F]AlF-NOTA-SC and therapeutic radioconjugates [177Lu]Lu-BL02 and [161Tb]Tb-BL02 were synthesized and evaluated. Radiolabeling efficiency, molar activity, and in vitro binding affinity were assessed. Specificity and uptake were evaluated in CXCR4-expressing U87.CD4.CXCR4 and MM.1S cells, with cytotoxic potential being analyzed via clonogenic survival assays. In vivo biodistribution and pharmacokinetics were evaluated in MM.1S xenograft mouse models, supported by longitudinal SPECT imaging. Results: All radioconjugates were obtained with high radiochemical purity (>98%). The constructs showed nanomolar affinity for human CXCR4; in vitro assays confirmed specific uptake in CXCR4-positive cells, and both therapeutic agents demonstrated dose-dependent cytotoxicity. In vivo, all compounds displayed comparable tumor uptake with low off-target accumulation. Co-injection studies confirmed consistent pharmacokinetics across agents, while SPECT/CT imaging demonstrated gradual tumor clearance of [177Lu]Lu-BL02 over seven days. Conclusions: The radiopharmaceutical trio [18F]AlF-NOTA-SC, [177Lu]Lu-BL02, and [161Tb]Tb-BL02 demonstrates the feasibility of a CXCR4-targeted theranostic approach for imaging and treating hematologic malignancies. The observed tumor washout highlights the need for further structural optimization to enhance tumor retention and therapeutic efficacy, providing a clear direction for future development toward clinical translation. Full article
(This article belongs to the Special Issue Advances in Theranostic Radiopharmaceuticals)
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16 pages, 1696 KB  
Article
Evaluation of Daughter Radionuclide Release from the 103Pd/103mRh In Vivo Generator for Targeted Auger Therapy
by Aicha Nour Laouameria, Cathryn H. S. Driver, Monika Buys, Elena Sergeevna Kurakina, Mátyás Hunyadi, Jan Rijn Zeevaart and Zoltan Szucs
Pharmaceuticals 2026, 19(1), 126; https://doi.org/10.3390/ph19010126 - 11 Jan 2026
Cited by 2 | Viewed by 1341
Abstract
Background/Objectives: The 103Pd/103mRh in vivo generator represents a promising Auger electron-emitting system, in which both parent and daughter radionuclides emit predominantly Auger electrons with minimal accompanying radiation. This study investigates the release dynamics of daughter radionuclides from the 103 [...] Read more.
Background/Objectives: The 103Pd/103mRh in vivo generator represents a promising Auger electron-emitting system, in which both parent and daughter radionuclides emit predominantly Auger electrons with minimal accompanying radiation. This study investigates the release dynamics of daughter radionuclides from the 103Pd/103mRh in vivo generator and evaluates the underlying mechanisms governing bond rupture and daughter retention. Methods: Cyclotron irradiation of rhodium foils was performed in two separate batches, followed by radionuclide separation using conventional wet chemistry and a novel dry distillation technique. The purified 103Pd radionuclide was used to radiolabel DOTA-TATE, phthalocyanine-TATE, and DOTA-TOC chelators. The resulting complexes were immobilized on Strata-X and Strata-C18 solid-phase extraction columns. Scheduled elution experiments were conducted to quantify the release of the 103mRh daughter radionuclide. Results: The measured 103mRh release rates were 9.8 ± 3.0% and 9.6 ± 2.7% from Strata-X columns with DOTA-TATE and phthalocyanine-TATE, respectively, and 10.5 ± 2.7% and 12.0 ± 0.5% from Strata-X and Strata-C18 columns, respectively, with DOTA-TOC. These values are significantly lower than the ~100% release predicted based on the reported Auger electron yield of 186%. One explanation for this difference could be potential inconsistencies in decay data that may require correction; this needs further investigation. The results further demonstrated that delocalized π-electrons, introduced via phthalocyanine-based chelation, did not mitigate daughter release. Conclusions: The low observed daughter nuclide release represents a favorable characteristic for the future clinical translation of the 103Pd/103mRh Auger emitter pair. The findings support the conclusion that Auger electron cascades, rather than nuclear recoil energy, dominate bond rupture processes. Full article
(This article belongs to the Special Issue Advances in Theranostic Radiopharmaceuticals)
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18 pages, 1585 KB  
Article
Affinity- and Format-Dependent Pharmacokinetics of 89Zr-Labeled Albumin-Binding VHH Constructs
by Simon Leekens, Peter Casteels, Tom Van Bogaert, Pieter Deschaght, Veronique De Brabandere, Christopher Cawthorne, Guy Bormans and Frederik Cleeren
Pharmaceuticals 2026, 19(1), 120; https://doi.org/10.3390/ph19010120 - 9 Jan 2026
Cited by 1 | Viewed by 1984
Abstract
Background/Objectives: NANOBODY® molecules (VHHs) are attractive vectors for radiopharmaceuticals due to their small size and high target affinity, but rapid clearance and pronounced kidney retention limit their therapeutic applicability. Binding to serum albumin is a widely used strategy to prolong circulation, yet [...] Read more.
Background/Objectives: NANOBODY® molecules (VHHs) are attractive vectors for radiopharmaceuticals due to their small size and high target affinity, but rapid clearance and pronounced kidney retention limit their therapeutic applicability. Binding to serum albumin is a widely used strategy to prolong circulation, yet the respective contributions of albumin-binding affinity and molecular format remain insufficiently defined. This study aimed to systematically evaluate how affinity and valency modulate VHH pharmacokinetics. Methods: Four monovalent albumin-binding VHHs spanning nanomolar to micromolar affinities and two bivalent constructs were engineered, generated by fusing an albumin-binding VHH to an irrelevant non-binding VHH. All constructs incorporated a site-specific cysteine for DFO* conjugation, enabling uniform zirconium-89 labeling with high radiochemical purity. Pharmacokinetics were assessed in healthy mice using serial blood sampling and positron emission tomography. Blood and kidney exposure were quantified by non-compartmental analysis. Results: All albumin-binding constructs showed increased systemic exposure and reduced kidney uptake relative to a non-binding control. Nanomolar-affinity binders reached maximal exposure, and further affinity increases (KD < ~100 nM) did not improve pharmacokinetics, suggesting a threshold. The micromolar binder showed intermediate exposure but still reduced renal retention compared with control. Valency effects were affinity-dependent. They were negligible at high affinity but pronounced at low affinity, where bivalency reduced systemic exposure and increased kidney uptake toward control levels. Conclusions: Albumin binding enables tuning of VHH pharmacokinetics in an affinity-dependent manner. Above an apparent affinity threshold, pharmacokinetics become format independent, whereas below this threshold, molecular format substantially influences systemic and renal disposition. Full article
(This article belongs to the Special Issue Advances in Theranostic Radiopharmaceuticals)
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Review

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20 pages, 1321 KB  
Review
Baseline PSMA PET/CT Biomarkers for Patient Selection in [177Lu]Lu-PSMA Radioligand Therapy: Clinical Promise, Methodological Heterogeneity and Future Standardization
by Grytė Galnaitienė, Matas Šimkus, Ieva Balčiūnaitė, Kornelija Lušaitė, Fang Wen, Marco Hoffmann, Matthias Saar, Felix M. Mottaghy, Donatas Vajauskas and Susanne Lütje
Pharmaceuticals 2026, 19(7), 1084; https://doi.org/10.3390/ph19071084 - 14 Jul 2026
Viewed by 566
Abstract
PSMA PET/CT imaging biomarkers are increasingly investigated as predictors of response and survival outcomes following [177Lu]Lu-PSMA radioligand therapy in prostate cancer. This review summarizes the current evidence and clinical relevance of these biomarkers. As [177Lu]Lu-PSMA radioligand therapy is increasingly [...] Read more.
PSMA PET/CT imaging biomarkers are increasingly investigated as predictors of response and survival outcomes following [177Lu]Lu-PSMA radioligand therapy in prostate cancer. This review summarizes the current evidence and clinical relevance of these biomarkers. As [177Lu]Lu-PSMA radioligand therapy is increasingly being introduced into earlier treatment lines of prostate cancer management, the identification of reliable imaging biomarkers for response prediction and outcome assessment is becoming increasingly important. Quantitative PSMA PET/CT parameters such as whole-body (WB) mean standardized uptake value (SUVmean), WB PSMA-positive tumor volume, and tumor load, as well as qualitative features including disease distribution and phenotype (e.g., visceral metastases and FDG-avid, PSMA-negative discordant lesions), have been associated with treatment response, progression-free survival, and overall survival. However, the clinical utility of these imaging biomarkers is limited by heterogeneous study designs, small cohorts, and a lack of standardization in image acquisition, quantification, and cutoff definitions. This review critically appraises available data on baseline PSMA PET/CT-based prognostic and potentially predictive biomarkers for RLT and identifies the methodological barriers that must be addressed before these biomarkers can be implemented in clinical practice. Full article
(This article belongs to the Special Issue Advances in Theranostic Radiopharmaceuticals)
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