Cyril Fersing

Introduction: Radioligand Therapy (RLT) targeting Prostate-Specific Membrane Antigen (PSMA) reshapes the therapeutic landscape of metastatic castration-resistant prostate cancer. However, the rapid systemic clearance of small-molecule radioligands directly affects circulation time and tumor exposure. Reversible albumin binding emerged as a practical strategy to extend circulation and modulate biodistribution. Among drug-derived Albumin-Binding Moieties (ABMs), Evans Blue (EB) and ibuprofen (Ibu) offer distinct approaches to improve pharmacokinetics and the therapeutic index. Methods: This review analyzes the design, synthesis, structure-activity relationships, and evaluation of PSMA radioligands incorporating EB- or Ibu-derived ABMs. Preclinical and clinical literature was examined, with emphasis on translational candidates. Results: EB confers strong albumin binding and markedly prolongs tumor residence, whereas Ibu enables more finely tunable interactions with albumin. The impact of linker, radionuclide, and albumin affinity on biodistribution, dosimetry, and therapeutic efficacy are essential to consider. Available data suggest that albumin binding is a tunable pharmacokinetic parameter rather than a binary property. Clinical experience with EB-PSMA-617 and SibuDAB demonstrates that increasing tumor absorbed dose through prolonged circulation is achievable but may increase irradiation of kidneys, bone marrow, and salivary glands. Discussion: These findings support the hypothesis that moderately strong, tunable albumin binding offers the most favorable therapeutic window. Stereochemical optimization of Ibu-derived ABMs and linker engineering illustrate how subtle structural changes can rebalance tumor uptake, clearance, and safety. Future radiopharmaceutical design will likely rely on iterative structure- pharmacokinetic optimization and dosimetry to define optimal albumin affinity. Conclusion: Overall, ABMs appear to be central tools for the design of next-generation PSMA radioligands and other radiopharmaceuticals.

The role of immunotherapy in oncohematology is well established. Monoclonal antibodies have undergone substantial development in recent years, targeting a wide range of molecules (including surface antigens, immune checkpoints, and cytokines) and have demonstrated clinical utility across various hematologic malignancies, including leukemias, lymphomas, and myelomas. The emergence of advanced therapy medicinal products (ATMPs), particularly chimeric antigen receptor (CAR) T cells, has provided an additional and promising therapeutic option. This rapidly evolving field continues to expand therapeutic possibilities. The objective of this literature review is to summarize novel immunotherapeutic strategies in oncohematology, including monoclonal antibody- and CAR T-cell-based approaches, and to review the key findings from recent clinical trials.

Radioligand therapy (RLT) targeting the prostate-specific membrane antigen (PSMA) has become a key treatment modality for metastatic castration-resistant prostate cancer. However, the rapid clearance and suboptimal tumor uptake of current smallmolecule PSMA ligands limit their therapeutic index. Incorporating reversible albuminbinding moieties (ABM), particularly 4-phenylbutyric acid (PBA)-derived groups, has emerged as a powerful strategy to modulate pharmacokinetics by prolonging systemic circulation, enhancing tumor uptake, and improving radiation dose delivery. This review summarizes the chemical and translational advances of PSMA-targeting radiopharmaceuticals integrating PBA-type ABM. It details structure-activity relationships governing albumin affinity and linker design across all major chemical series. Emphasis is placed on the most clinically advanced candidates, i.e. PSMA-Trillium, HTK03170, Ludotadipep, P17-088, and CTT1403, highlighting their pharmacokinetics, tumor targeting, safety profiles, and early clinical outcomes. Key determinants of in vivo performance, including affinity for albumin and PSMA, polarity and length of linker elements, are examined in the context of tumor-to-kidney dose ratios and therapeutic efficacy. Collectively, PBA-derived ABM have proven highly effective but require careful tuning, as excessive albumin binding could lead to prolonged hematologic exposure and kidney irradiation, whereas insufficient affinity reduces therapeutic gains. The most successful ligands achieve a balanced interplay between albumin binding, PSMA affinity, and controlled renal clearance. As next-generation α- and β-emitters enter clinical development, optimized ABM-containing radiopharmaceuticals are expected to deliver higher tumor doses with improved safety, supporting their growing role in precision therapy for advanced prostate cancer.

Les maladies tropicales négligées causées par les protozoaires kinétoplastidés du genre Leishmania et Trypanosoma représentent une menace pour près d’un demi-milliard de personnes en zone intertropicale, entrainant jusqu’à 50 000 décès par an. Parmi les molécules en développement clinique pour traiter ces pathologies, le fexinidazole est une prodrogue appartenant à la famille des 5-nitroimidazoles et qui exerce son action anti-infectieuse via une étape de bioactivation catalysée par des nitroréductases (NTR) parasitaires, enzymes dont le co-facteur est une flavine. Afin d’identifier de nouveaux nitrohétérocycles antiparasitaires substrats des NTR, une petite chimiothèque d’imidazo[1,2-a]pyridines synthétisées au laboratoire a subi un criblage in vitro ayant conduit à l’identification d’une molécule Hit, à la fois active sur Leishmania donovani et Trypanosoma brucei brucei. Ce composé a servi de point de départ à un travail de pharmacomodulation, dans un premier temps en position 8 du cycle imidazo[1,2-a]pyridine : l’introduction de groupements variés à l’aide de réactions de couplage pallado-catalysées de Suzuki-Miyaura, Sonogashira et Buchwald-Hartwig ou des réactions de SNAr, a permis de mettre en lumière plusieurs composés « tête de série » au profil biologique nettement amélioré. Dans un second temps, le travail de pharmacomodulation entrepris a été étendu aux positions 2, 3 et 6 du cycle imidazo[1,2-a]pyridine en vue de compléter les données de relations structure-activité, d’étudier en particulier l’impact du potentiel rédox et d’optimiser les paramètres physico-chimiques et pharmacocinétiques in vitro des meilleurs composés.

Nuclear medicine is a medical specialty combining parenteral radioactive drug handling and complex clinical workflows, making systematic process-related incident (PRI) analysis essential to support healthcare quality improvement. This study reports a four-year single-center retrospective analysis of PRIs in a nuclear medicine department and describes the development and implementation of a scenario-based radiopharmacy training program for nuclear medicine technologists (NMTs) derived from these findings. PRIs were extracted from the institutional reporting system and categorized according to a structured classification. Training scenarios were designed from recurrent radiopharmacy-related PRIs, and their impact was evaluated using a knowledge questionnaire administered pre and post training. A total of 223 PRIs were analyzed, of which 38.6% (n = 86) were related to the radiopharmaceutical circuit. Among these, 28.3% occurred exclusively within the radiopharmacy cleanroom. Administration (19%), dispensing (15%), delivery and reception (15%), and preparation and quality control (15%) of radiopharmaceuticals were the most frequently involved stages. No PRI exceeded a moderate criticality level. Eight NMTs participated in the training program, consisting of an analysis of videos depicting the developed scenarios. The mean knowledge score increased significantly from 7.51/10 before training to 8.46/10 four weeks after training (p = 0.02), with marked improvements in hygiene- and radioactivity-related topics. These results support the use of retrospective PRI analysis as an operational basis for specific, scenario-based training to strengthen safety practices in radiopharmacy settings.

The aim of the study was to develop and assess alternative radiolabeling strategies for SOMAKIT-TOC using gallium-68, with the aim of improving cost-efficiency by increasing the number of examinations per cold kit while maintaining radiochemical quality suitable for clinical use. Four protocols were evaluated using triplicate test radiolabelings: (1) the reference method using a single generator and a full kit; (2) dual-generator elution into a full kit; (3) single-generator elution into two sequentially radiolabeled aliquots from one kit; and (4) dual-generator elution into two sequentially radiolabeled aliquots from one kit. Radiochemical purity (RCP) was assessed by radio-thin layer chromatography (rTLC) and radio-high performance liquid chromatography (rHPLC), and radiochemical stability was monitored over 4 hours. Additional quality controls parameters included pH, sterility, and peptide integrity in aliquot solution. Procedures 1 and 3 were further assessed in clinical routine. All protocols yielded radiopharmaceuticals with mean RCP values above 95% by rTLC. Procedure 2 significantly increased the final activity compared with Procedure 1. Procedure 3 enabled doubling the number of examinations per kit while maintaining RCP comparable to the reference method Procedure 4 showed greater variability. Radiolabeled products remained stable over 4 hours as assessed by rTLC, although rHPLC revealed a gradual decrease in purity. In clinical use, Procedure 3 allowed 94 preparations that met diagnostic needs, though 33% had RCP between 80 and 95%. Aliquoting a single cold kit for dual radiolabeling using one generator is feasible and cost-effective, although it is associated with greater RCP variability. Dual-generator strategies yield higher activity but may further compromise RCP. Further optimization is required to improve robustness of off-label protocols while preserving the highest product quality.

The growing use of experimental radiopharmaceuticals for targeted radionuclide therapy (TRT) highlights the need for robust “in house” radiolabeling protocols. Among these, PSMA-ALB-56 is a PSMA ligand incorporating an albumin-binding moiety to enhance pharmacokinetics, which showed promise for prostate cancer treatment. This study investigated manual radiolabeling conditions of this vector molecule with lutetium-177 and developed a corresponding automated synthesis protocol. Manual experiments on low activities explored buffer systems and antioxidants, identifying sodium acetate buffer and L-methionine as optimal, achieving radiochemical purities above 97% with excellent stability over 48 h. However, when these conditions were transposed directly to an automated process on a GAIA^® module with activities > 2 GBq, radiochemical purity dropped below 70% due to significant radiolysis. This result emphasized that conditions optimized at low activities are not directly transferable to high-activity automated production, and highlighted the crucial role of antioxidant concentration. An optimized automated method was subsequently developed, integrating a solid-phase extraction purification step, higher antioxidant levels during radiolabeling and formulation, and a larger final product volume. These changes led to radiochemical purities above 98.9% and excellent product stability over 120 h for 3 test batches. The presence of high concentrations of methionine and ascorbic acid was essential to protect against radiolysis. This work underscores the importance of adjusting radiolabeling strategies during process scale-up and confirmed that antioxidant concentration is essential for successful ¹⁷⁷Lu radiolabeling. The optimized automated method developed here for [¹⁷⁷Lu]Lu-PSMA-ALB-56 may also be adapted to other radiopharmaceuticals in development for TRT.

Invasive lobular carcinoma (ILC) of the breast is a rare subtype of breast cancer with distinct metastatic patterns. Although gastrointestinal metastases are rare, they can occur years after initial treatment. This case highlights the diagnostic challenges and management of late‐onset gastric metastases. A 68‐year‐old woman with a history of ILC treated 20 years earlier presented with elevated tumor markers. [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) revealed hypermetabolic lesions in the stomach and esophagus in this patient with previously diagnosed gastritis and gastroesophageal reflux disease. Endoscopy and biopsies confirmed the presence of metastatic ILC in the stomach. Adjustment of treatment, including exemestane and everolimus, followed by paclitaxel and tamoxifen, resulted in partial disease control. Late‐onset gastrointestinal metastases of ILC are uncommon and require special vigilance, particularly in patients with associated benign gastrointestinal pathologies, which may delay diagnosis. Persistent or new‐onset gastrointestinal symptoms in breast cancer patients warrant thorough evaluation, including FDG PET/CT imaging and histological confirmation.

Introduction: Automated radiolabeling of gallium-68-labeled experimental radiopharmaceuticals is crucial for ensuring high reproducibility and regulatory compliance in clinical settings. FAP-2286, a promising DOTA-pseudopeptide targeting the tumor microenvironment, has demonstrated superior tumor retention compared to quinoline-based analogs, making it an attractive theranostic agent. This study aimed to optimize and automate the preparation of [⁶⁸Ga]Ga-FAP-2286 on the GAIA^® synthesizer, ensuring high radiochemical purity (RCP) and radiochemical yield (RCY).Methods: Manual radiolabeling assays were initially performed to identify optimal reaction conditions, varying buffer, antioxidant, vector amount, heating time, and purification methods. The selected conditions were then adapted to an automated protocol using a GAIA^® module. A strong cation exchange (SCX) cartridge for ⁶⁸Ga pre-concentration and a solid-phase extraction (SPE) step for final purification were included in the process. RCY, RCP, and stability over 4 h were assessed using radio-HPLC and radio-TLC. Additionally, the applicability of the optimized automated method was evaluated for 3BP-3940, a structurally related pseudopeptide.Results: Initial optimization studies identified sodium acetate buffer 0.1 M with methionine as an antioxidant, 25 μg of FAP-2286, and a 4-min heating time as the best manual radiolabeling conditions, achieving a RCP > 98%. In the automated synthesis, adjustments were made, including doubling the vector amount and extending heating to 9 min, resulting over three test-batches in a moderate RCY of 59.85 ± 3.73% and a RCP just over 94% up to 4 h after the end of synthesis. Importantly, the method was successfully transposed to [⁶⁸Ga]Ga-3BP-3940, yielding better RCY (75.62 ± 11.76%), RCP and stability profiles (> 95.95% over 4 h).Conclusion: This study established a robust, automated protocol for the synthesis of [⁶⁸Ga]Ga-FAP-2286, ensuring high purity, reproducibility, and compatibility with clinical applications. The method’s successful adaptation to 3BP-3940 highlights its versatility for such radiopharmaceuticals, supporting the broader implementation of automated theranostic agent production in nuclear medicine.