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Preclinically, radiopharmaceuticals are currently mainly evaluated in two-dimensional (2D) cell models, which lack clinical features that are relevant for accurate evaluation of targeted radionuclide therapy (TRT) responses. The development of three-dimensional (3D) cell models in the last years offers opportunities to overcome at least parts of the limitations of 2D cell models, but such 3D cell models are currently only rarely used in nuclear medicine research. Moreover, the comparison between 2D and 3D cell models, aimed at demonstrating the potential added value of 3D cell models, is even more scarce. To fill this gap and promote the use of more clinically relevant 3D cell models in nuclear medicine research, we performed such a comparative study. For this, we developed and evaluated 3D cell models derived from the prostate-specific membrane antigen (PSMA)-expressing human cancer cell lines LNCaP and PC3-PIP, by culturing these cells in anti-adhesive round bottom plates (“bio-spheroids”) or by culturing LNCaP cells in Matrigel (MG) or Noviogel-P5K (NG) domes (”MG-spheroids” or “NG-spheroids”). Hereafter, PSMA expression levels and [111In]In-PSMA-I&T uptake were determined and compared between 3D and 2D cell models. Additionally, we assessed cell viability of 3D- versus 2D-cultured cells after external beam radiation therapy (EBRT) and PSMA-TRT using [177Lu]Lu-PSMA-I&T. No significant differences in viability were observed between bio-spheroids versus 2D cell models after EBRT and PSMA-TRT, neither in LNCaP nor in PC3-PIP cells. In contrast, LNCaP MG-spheroids had a significantly better response to PSMA-TRT in comparison to the 2D-cultured cells. This was despite a lower PSMA expression level and lower [111In]In-PSMA-I&T uptake in the MG-spheroids. Importantly, no significant difference in radiosensitivity was observed between these MG-spheroids and the 2D cell model. Despite lower PSMA expression levels and lower radiopharmaceutical uptake in LNCaP MG-spheroids, and albeit similar radiosensitivity, PSMA-TRT induced a stronger reduction in viability in the MG-spheroids in comparison to the 2D-cultured cells. In contrast, no differences were observed in PSMA-TRT efficacy between bio-spheroids and the 2D cell model. The aforementioned leads to the hypothesis that biological factors important for TRT, e.g. cross-radiation and radiopharmaceutical retention within the 3D cell structure, are better represented in MG-spheroids where cell-cell interactions are already formed prior to radiopharmaceutical incubation. The online version contains supplementary material available at 10.1186/s13550-026-01393-0.

Immuno-positron emission tomography (immuno-PET) imaging is emerging as a highly promising technique for the non-invasive diagnosis of a wide range of pathological conditions, particularly in oncology and immunology. This molecular imaging modality enables the visualization, characterization, and quantification of biological processes at a cellular and molecular level. Immuno-PET relies mostly on the administration of monoclonal antibodies (mAb) labeled with positron-emitting radionuclides. These antibodies are specifically designed to bind to antigens that are overexpressed on tumor cells or involved in pathological non-neoplastic processes, such as inflammatory or autoimmune diseases. Numerous disease-associated antigens have been identified and are currently being explored as potential molecular targets for immuno-PET, paving the way for more personalized diagnostic and treatment approaches. This technique offers significant potential in the context of theranostic, as it allows for the simultaneous assessment of both diagnostic and therapeutic parameters. It is particularly useful for predicting and monitoring the pharmacokinetics and biodistribution of targeted therapies, thereby helping to optimize therapeutic efficacy while minimizing adverse effects. Among the various radioisotopes available, zirconium-89 (89Zr) has gained attention as a particularly suitable candidate for mAb labeling due to its favorable physicochemical characteristics such as its half-life (78.4 h), which matches well with the slow kinetics of intact antibodies, and its appropriate positron emission profile for high-resolution imaging. Despite the growing interest in immuno-PET and the increasing number of radiolabeling protocols described in the literature, the clinical implementation of 89Zr-labeled mAbs faces numerous challenges. These include logistical and technical hurdles, but more significantly, regulatory obstacles that vary across countries and between regulatory authorities, particularly within Europe. Such disparities hinder the harmonization of clinical trials and limit access to immuno-PET technologies for many research centers. In this review, we aim to provide an overview of the current clinical applications of 89Zr-labeled mAbs, based on published studies and ongoing trials, and highlight the key challenges that need to be addressed to expand access to this powerful imaging modality.

In this study, we aimed to identify oncofetal antigens expressed in prostate cancer and systematically examine their potential role using theranostic approaches. Cell surface oncofetal antigens are expressed to a limited extent in adult cells and may be variably expressed in tumor cells. The fact that oncofetal proteins are not expressed in healthy cells minimizes the risk of systemic toxicity, especially when using targeted therapies. Cell surface oncofetal proteins identified in prostate cancer are CEACAM5, Trop-2 (TACSTD2), Glypican-3 (GPC3), ROR1 (NTRKR1), and 5T4 (TPBG). In accordance with PRISMA guidelines, we conducted a systematic review of peer-reviewed articles indexed in Scopus, PubMed and Web of Science databases until February 10, 2025. Studies evaluating the expression, biological role, and therapeutic relevance of cell surface oncofetal antigens in PC were included. Data extraction focused on their functional role in prostate cancer, associated radiopharmaceuticals, and clinical or preclinical therapeutic strategies. Five key oncofetal proteins: CEACAM5, Trop-2, ROR1, GPC3, and 5T4 have been consistently identified in the literature. These proteins have been associated with aggressive PC subtypes, including neuroendocrine and castration-resistant forms; and are linked to key signaling pathways such as Wnt/β-Catenin, EMT, and PI3K/AKT. Several investigational agents targeting these antigens, including antibody-drug conjugates (ADCs), CAR-T cells and radiolabeled imaging probes (e.g. 68Ga, 89Zr, 64Cu, 225Ac) are being developed and evaluated in both preclinical and early clinical settings. CEACAM5, Trop-2, 5T4, GPC3, and ROR1 oncofetal proteins are variably expressed in advanced prostate cancer. Therapeutics and radiopharmaceutical imaging agents targeting these proteins are in development. Though provocative findings are apparent, considerable clinical research is needed to determine the value of targeting these proteins. The online version contains supplementary material available at 10.1186/s13550-026-01396-x.

Scandium radionuclides are emerging theranostic radionuclides that offer matched diagnostic and therapeutic emissions for targeted applications in nuclear medicine. For their safe and effective clinical use, it is crucial to obtain preparations with very high radiochemical purity, which in turn relies on carefully optimized physical separation and chemical purification strategies. A selective and clinically attractive method for purification is ion-exchange solid-phase extraction; however, its performance and expected resin lifetime under high radiation doses and repeated separation cycles remains insufficiently considered. This study provides a critical evaluation of the radiation stability and separation performance of the N, N,N',N'-tetra(2-ethylhexyl)diglycolamide (TEHDGA) ion-exchange resin. Monte Carlo simulations in RayXpert® show that assuming 1 GBq 44Sc and 3.7 GBq 47Sc initial activities (possible theranostic activities) a total absorbed dose of ~ 1 kGy could be expected for 44Sc and ~ 5 kGy for 47Sc in one purification experiment. EPR spectra show that after irradiation the TEHDGA resin does not form room temperature stable radicals; however, the resin appears to change its chemical structure upon irradiation with electrons in a nitric acid environment, as indicated by ATR-FTIR measurements. However, these chemical changes can be estimated to have little-to-no effect on the practical application of TEHDGA in scandium ion purification, yielding separation efficiency from contaminants of at least 99% for resin irradiated in 2.5 M HNO3, whereas irradiation in air yielded a minimum separation efficiency of 96%. No clear changes in selectivity, ion-exchange capacity or recoverability have been observed. TEHDGA resin can be deemed suitable for theranostic scandium radionuclide purification from metallic contaminants; however, further research is needed to assess the possible transient effects of short-lived radiolysis intermediates during practical scandium radionuclide purification.

Vascular endothelial growth factor receptor-3 (VEGFR-3) is overexpressed in tumor-induced lymphangiogenesis. TMVP1446/GS5 is a peptide analogue specifically targeting VEGFR-3, developed through substitution of the original peptide TMVP1446 with non-natural amino acids and terminal modification. This study aimed to evaluate the potential of 68Ga-labeled TMVP1446/GS5 as a probe for imaging primary tumors and metastatic lymph nodes. [68Ga]Ga-DOTA-TMVP1446/GS5 exhibited excellent labeling yield and radiochemical purity (RCP). Radio-HPLC analysis demonstrated comparable radiochemical and chemical stability to the original probe. Although stability in mouse plasma remained limited, [68Ga]Ga-DOTA-TMVP1446/GS5 exhibited modestly improved metabolic stability than the original probe. Cellular assays and surface plasmon resonance (SPR) analysis showed comparable or slightly higher binding affinity to VEGFR-3 relative to the original probe. In B16F10 subcutaneous xenografts, [68Ga]Ga-DOTA-TMVP1446/GS5 showed stronger and more sustained tumor uptake compared to the original probe, along with extended in vivo retention. At 2 h post-injection, tumor uptake reached 4.90 ± 0.36%ID/g, approximately five times of the original probe (1.03 ± 0.06%ID/g). In B16F10 footpad lymph node metastasis model, [68Ga]Ga-DOTA-TMVP1446/GS5 enabled clear visualization of metastatic lymph nodes. [68Ga]Ga-DOTA-TMVP1446/GS5 showed enhanced and sustained tumor uptake and extended in vivo retention. It provided relatively superior imaging of both primary tumors and metastatic lymph nodes at later time points, suggesting its potential for further research.

Osteoporosis is a chronic skeletal disorder characterized by reduced bone mineral density and disrupted bone microarchitecture, affecting over 200 million individuals worldwide. The lumbar spine, containing the largest volume of metabolically active trabecular bone, is particularly vulnerable to osteoporotic degeneration and compression fractures. This narrative review examines recent advances in imaging modalities for lumbar spine osteoporosis assessment, emphasizing the diagnostic utility and emerging clinical applications of ¹⁸F-sodium fluoride (NaF) positron emission tomography/computed tomography (PET/CT). A comprehensive narrative review was conducted, synthesizing findings from pivotal studies investigating conventional imaging methods and newer PET-based technologies for osteoporosis evaluation. Particular focus was given to studies utilizing quantitative and kinetic PET biomarkers for assessing bone metabolic activity with ¹⁸F-NaF. While dual-energy X-ray absorptiometry (DXA) remains the clinical standard for bone mineral density assessment, it has significant limitations including poor spatial resolution, lack of three-dimensional capability, and inability to differentiate cortical from trabecular bone. In contrast, ¹⁸F-NaF PET/CT demonstrates superior image quality, rapid tracer kinetics, and quantitative assessment of regional osteoblastic activity. Studies show strong correlations between ¹⁸F-NaF uptake and bone turnover markers, mineral density measurements, and therapeutic response. Kinetic modeling approaches provide detailed insights into bone remodeling dynamics, supporting personalized treatment planning and prognostic assessment. Diagnostic performance studies report area under the receiver operating characteristic curves as high as 0.96 for osteoporosis detection when evaluated against DXA-derived BMD, though no study has yet compared both modalities against an independent gold standard such as fracture outcomes. ¹⁸F-NaF PET/CT offers optimal clinical applications for early treatment response monitoring, evaluation of patients with discordant clinical risk and DXA findings, pre-surgical assessment in patients with borderline bone density, and investigation of complex metabolic bone disorders. Ideally, ¹⁸F-NaF PET/CT should be utilized in a complementary fashion to DXA. Primary barriers to clinical adoption include cost, limited accessibility, and absence of standardized kinetic modeling protocols. Future research should focus on establishing reference ranges across age and sex demographics, validating fracture prediction models, and determining cost-effectiveness thresholds for specific clinical scenarios such as high-risk patients with discordant DXA and fracture history.

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The Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) scanner combines two diagnostic imaging modalities, providing information on anatomy and physiology. Beneficial diagnosis areas are epilepsy ([[Formula: see text]F]Fluorodeoxyglucose (FDG)) and cancer recurrence ([[Formula: see text]C]methionine (MET)), where subject motion during PET acquisition reduces image quality, potentially compromising diagnostic accuracy. This project aimed to evaluate the impact of PET data-driven motion correction (ddMC) of these clinical PET radiotracers and to assess, for the first time, whether the automatic motion categorization reflects motion levels impacting the image quality. Eighty-nine PET scans (66 [[Formula: see text]C]MET, 23 [[Formula: see text]F]FDG) were reconstructed with ddMC and without motion correction (noMC) using the research software lmDuetto toolbox (GE Healthcare, Chicago, IL, USA), and were automatically categorized into motion groups. MRI images were segmented, and the regions of interest (ROIs) transferred to the PET space. The effect of ddMC was analyzed by relative signal differences between ddMC and noMC. Motion estimation and categorization were evaluated by normalized cross correlation (XC) over time and the proposed cumulative displacement-time histogram (cDTH). Overall, ddMC increased signal values within cortical ROIs compared to noMC. In the high motion category, median relative mean signal differences were 0.61% (0.41-0.80%) for [[Formula: see text]F]FDG and 0.70% (0.61-0.79%) for [[Formula: see text]C]MET. The XC improved ([[Formula: see text]F]FDG: 0.80 to 0.97, [[Formula: see text]C]MET: 0.85 to 0.98). Low and medium motion groups had lesser impact, indicating motion correction is most relevant for high motion. The XC and cDTH identified subjects whose motion classification should be revised. In conclusion, the results confirm previous findings with ddMC using [[Formula: see text]F]FDG and demonstrate its suitability for lower-accumulating [[Formula: see text]C]MET. The automatic motion categorization needs re-evaluation to better reflect motion affecting PET image quality.

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Quantitative 177Lu-SPECT allows for patient specific dosimetry, but due to the limited spatial resolution absorbed doses (AD) can be underestimated. Implementation of the Lucy-Richardson deconvolution (LRD) algorithm for spill-over correction in PET has been investigated. Therefore, the aim of this study was to extend the potential application of LRD to 177Lu-SPECT based tumor dosimetry. The NEMA IEC Body Phantom (foreground-to-background ratio 8:1, 237:30 kBq/mL) was measured according to the local imaging and reconstruction protocol. The two main parameters of LRD, sigma and number of iterations, were determined in two steps. First, a matched filter resolution analysis was conducted on the ground truth activity distribution as segmented from the NEMA IEC Body Phantom data to define the sigma of a 3D Gaussian point-spread-function, which describes the system's spatial resolution. Secondly, using this sigma, a suitable number of LRD iterations was determined by comparing sphere recovery coefficients (RC) and signal-to-noise ratios. The selected parameters were then applied to the reconstructed SPECT series (24, 48, and 72 h post-injection) of 20 patients who received either [177Lu]Lu-DOTA-TATE (n = 10) or [177Lu]Lu-PSMA-I&T (y = 10) treatment, in order to evaluate its impact on AD estimates. Lesion AD from the original reconstruction (OR) and OR + LRD were estimated using MIM SurePlan™ MRT. The AD from OR, OR + LRD, and OR + RC (phantom-based recovery correction based on volume) were compared. A sigma of 6.0 mm and four iterations resulted in an average improvement of 18.9 ± 4.7% and 17.4 ± 7.6% in the sphere recovery coefficients and the signal to noise ratio, respectively. In total, 98 lesions were evaluated ([177Lu]Lu-DOTA-TATE: n = 42) ([177Lu]Lu-PSMA-I&T: y = 56). For OR + LRD and OR + RC an average increase of 22 ± 12% and 57 ± 36% of tumor AD was found. OR + LRD increased AD compared to OR, independent of administered radiopharmaceutical and lesion location. This study suggests that implementing LRD may be a promising option for image-based spill-over correction in 177Lu-SPECT based dosimetry. Further studies are necessary to investigate the effect of different PVC methods, such as LRD or phantom-based correction factors, on overall uncertainty of lesion ADs.

Breast cancer (BC) is a biologically heterogeneous disease, and no single imaging modality captures the full spectrum of phenotypes across all stages of the disease. This review summarizes advances in receptor-targeted nuclear imaging approaches that support patient stratification, treatment selection and response monitoring. We provide a comprehensive review of preclinical and clinical studies of PET and SPECT radiopharmaceuticals targeting BC-relevant biomarkers on tumor cells and within the tumor microenvironment, with emphasis on clinical use cases, practical limitations and theranostic translational readiness. Conventional imaging modalities and [18F]FDG PET/CT remain central to staging but can be limited by poor specificity and reduced sensitivity for small lesions. Although anatomical (RECIST) and metabolic (PERCIST) response criteria remain central in routine response assessment, their application in BC can be challenging, particularly in bone-predominant disease and in the presence of marked inter-lesional heterogeneity. Receptor-mediated nuclear imaging enables non-invasive, whole-body phenotyping beyond biopsy and maps spatial heterogeneity. Clinical progress has been achieved for steroid receptors (ER/PR/AR), HER2, GRPR and SSTR2 imaging, and extends to stromal targets such as FAP (FAPI tracers). Emerging targets, including CXCR4, NTSR1, NPY1R and TROP-2, further broaden the theranostic landscape, particularly in settings where biomarker profiles are heterogeneous or evolve over time. Multi-target imaging strategies may better address intra- and inter-lesional heterogeneity. Larger prospective cohorts are needed to define diagnostic performance, clinical relevance and theranostic value in BC.

Despite the clinical implementation of Nectin-4-targeted antibody-drug conjugates (ADCs) and radioligand therapies (RLTs), their therapeutic window is often restricted by systemic toxicities and the emergence of drug resistance. To circumvent these limitations, we developed [177Lu]Lu-DOTA-AC-SP, a novel peptide-based radiopharmaceutical specifically engineered for the targeted treatment of Nectin-4-expressing malignancies. The synthesis of [177Lu]Lu-DOTA-AC-SP was achieved with high radiochemical purity and excellent stability in vitro. Pharmacokinetic evaluations revealed a favorable profile characterized by high binding affinity and rapid systemic clearance. In vivo biodistribution studies demonstrated significant tumor accumulation and prolonged retention, resulting in superior target-to-background ratios. Furthermore, [177Lu]Lu-DOTA-AC-SP exhibited robust anti-tumor efficacy in Nectin-4-positive models, maintaining an excellent safety profile with minimal off-target effects. These findings characterize [177Lu]Lu-DOTA-AC-SP as a potent and safe therapeutic candidate for Nectin-4-positive tumors. Its favorable pharmacokinetic properties and significant therapeutic index support its potential clinical translation as a next-generation treatment for urothelial carcinoma (UC).

The clinical standard practice of [177Lu]Lu-PSMA-617 therapy is a single injection per treatment cycle, with 6 weeks between cycles. While clinical schedules currently utilize single-bolus cycles, splitting a treatment cycle into multiple smaller injections has demonstrated benefits in other radionuclide therapies, preclinically and in clinical studies. Potential mechanisms for improved therapeutic efficacy include receptor recycling, receptor upregulation, or targeting new cell growth between fractions. This study aims to investigate the effects on tumor size and animal survival, in a mouse model of prostate cancer, of fractionating [177Lu]Lu-PSMA-617 therapy compared to the same total activity in a single injection. BALB/c mice bearing subcutaneous LNCaP prostate cancer tumors, below 650 mm3 in volume, were treated with either 1 × 30 MBq, 2 × 15 MBq (24-hour window), or 2 × 15 MBq (6-day window). SPECT/CT imaging showed a higher, but not significantly so, tumor uptake in the 24-hour window group than in the unfractionated one. Differences in tumor sizes were primarily visible during regrowth after therapy, with significantly smaller relative tumor sizes in the 24-hour window group compared to the unfractionated group day 89–95 post inoculation. The median survival for the 24-hour group (71.5 days) was significantly longer than that of the unfractionated group (46 days; p = 0.024). The 6-day group tumor sizes and survival came close to the 24-hour one, but was not significantly better than the unfractionated group. This study demonstrates that fractionation gives therapeutic benefit in an animal model of [177Lu]Lu-PSMA-617 therapy of prostate cancer for tumors in this size range. A shorter 24-hour window outperformed a longer of 6 d between fractions. The outlook for clinical translation will depend on if the mechanism is relevant at conditions, blood ligand concentration etc., that differs between the animal model and human patients. The online version contains supplementary material available at 10.1186/s13550-026-01417-9.

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A position paper released by the European Association of Nuclear Medicine emphasised the need for multidisciplinary engagement to establish dosimetry-based personalised treatment in Radionuclide therapy (RNT). The uncertainty analysis results often ignored in routine clinical practice should be incorporated into the dose calculations to improve the efficacy and accuracy of treatment. In this study, patients with haematological malignancies undergoing radioimmunotherapy were evaluated. Our study aimed to calculate the uncertainties associated with each parameter of the single time point (STP) dosimetry chain and compare the with multiple time points (MTP) in the bone marrow and liver results. 28 patients received an intravenous injection of 111In-besilesomab (0.17 ± 0.01GBq) for pre-therapeutic dosimetry and were subsequently treated with 90Y-besilesomab(2.43 ± 0.53GBq). A dosimetry analysis was performed on bone marrow (BM) and liver with MTP and STP. We investigated the uncertainty in population mean effective half-life, volume, recovery coefficient, counts, measured activity, fitting parameters, time-integrated-activity, S-factors, and absorbed dose (AD) for a group of patients. The mean absorbed dose per unit administered activity (DpA) to BM was 5.8 ± 1.7 mGy/MBq with MTP and 5.8 ± 1.6 mGy/MBq with STP, and to the liver was 2.9 ± 1.9 mGy/MBq with MTP and 3.1 ± 2.4 mGy/MBq with STP. The mean fractional uncertainty associated with total absorbed dose to BM was 13.18 ± 3.46% with MTP and 18.75 ± 3.22% with STP, and to liver was 5.77 ± 3.13% with MTP and 49.78 ± 25.36% with STP. A moderate positive relationship (R2 = 0.7) was noted between post-injection acquisition time and AD uncertainty with STP for BM, whereas a strong positive relationship (R2 = 1) was noted for the liver. The absorbed dose uncertainty in STP was significantly higher compared to the MTP. Incorporating the uncertainty analysis for STP dosimetry parameters in routine clinical practice is strongly recommended. The accuracy in the acquisition time, population-based half-life and fitting function for time activity curve is vital for minimising uncertainty in STP dosimetry, which is less time-consuming and easier to implement in clinical practice than MTP.

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