Search Results (419)

Radionuclide molecular imaging of epidermal growth factor receptor (EGFR) expression might permit the selection of patients for EGFR-targeting therapies. Designed ankyrin repeat protein (DARPin) E01 with a high affinity to the ectodomain III of the EGFR is a possible EGFR imaging probe. The goal of this study was to evaluate the potential of radiolabeled DARPin E01 for in vivo imaging of EGFR. DARPin E01 containing the (HE)₃-tag was site-specifically labeled with a residualizing ^99mTc (using ^99mTc]Tc(CO)₃). Two methods providing non-residualizing ¹²³I labels, direct electrophilic radioiodination and indirect radioiodination using [¹²³I]I-para-iodobenzoate (PIB), were tested. [^99mTc]Tc-(HE)₃-E01 and [¹²³I]I-(HE)₃-E01-PIB preserved specific binding to EGFR-expressing cells and affinity in the single-digit nanomolar range. Direct labeling with ¹²³I resulted in a substantial loss of binding. In vitro cellular processing studies showed that both [^99mTc]Tc-(HE)₃-E01 and [¹²³I]I-(HE)₃-E01-PIB had rapid binding and relatively slow internalization. Evaluation of [^99mTc]Tc-(HE)₃-E01 biodistribution in normal CD1 mice showed that its hepatic uptake was non-saturable, suggesting that this tracer does not bind to murine EGFR. A side-by-side comparison of biodistribution and tumor targeting of [^99mTc]Tc-(HE)₃-E01 and [¹²³I]I-(HE)₃-E01-PIB was performed in Nu/j mice bearing EGFR-positive A-431 and EGFR-negative Ramos human cancer xenografts. Both radiolabeled DARPins demonstrated EGFR-specific tumor uptake. However, [¹²³I]I-(HE)₃-E01-PIB had appreciably lower uptake in normal organs compared to [^99mTc]Tc-(HE)₃-E01, which provided significantly (p < 0.05) higher tumor-to-organ ratios. Gamma-camera imaging confirmed that [¹²³I]I-(HE)₃-E01-PIB demonstrated a higher imaging contrast in preclinical models than [^99mTc]Tc-(HE)₃-E01. In conclusion, DARPin (HE)₃-E01 labeled using a non-residualizing [¹²³I]I-para-iodobenzoate (PIB) label is the preferred radiotracer for in vivo imaging of EGFR expression in cancer. Full article

Background/Objectives: The role of α-synuclein (α-syn) in the pathogenesis of Parkinson’s disease (PD) or neurodegenerative diseases such as Lewy body dementia (LBD) and multiple system atrophy (MSA) is commonly accepted. Through different physiological dysfunctions, abnormal forms of α-syn are generated. These abnormal aggregates accumulate and alter pre- and postsynaptic transmission, in particular that of dopamine. Thus, the development of a diagnostic biomarker of synucleinopathies remains crucial and challenging. The development of an α-syn positron emission tomography (PET) radiopharmaceutical may be suitable to early diagnose and stratify patients, follow up disease progression, and evaluate future therapies. Methods: To develop a selective α-syn PET tracer, we synthesized an original series based on alkynyl(aza)indoles. Fifteen final ligands were synthesized bearing indoles or azaindoles from one side of the alkyne and a substituted phenyl ring for the opposite side of the alkyne. The final ligands were tested to determine Ki and/or Kd toward α-syn, tau, and Aβ. Results: The SAR showed that the indole series exhibited moderate to low affinity for α-syn and, moreover, lower Ki toward Aβ and tau (i.e., compound 39, Ki_(αsyn) 21.7 nM, Ki_(Aβ) 64.4 nM, Ki_(Tau) 27.6 nM), highlighting the low potency of these series to afford an α-syn tracer. The introduction of a nitrogen on the different positions of the phenyl to obtain the corresponding azaindoles resulted for most of the compounds in better affinity for α-syn and selectivity towards Aβ compared to the indole analogs (i.e., compound 43, Ki_(αsyn) 4.7 nM, Ki_(Aβ) 24.4 nM, and Ki_(Tau) 4.61 nM). A fluorinated azaindole derivative was prepared with a view to obtaining a ¹⁸F tracer and exhibited the highest affinity for α-syn but without selectivity against tau and Aβ. The radiosynthesis of [¹⁸F]45 was performed in a two-step procedure starting from the tosylated and protected precursor. [¹⁸F]45 was obtained in 85 ± 5 min with a radiochemical yield of 32 ± 3%. Molar activity, determined from a calibration with stable 45, was around 130 GBq/µmole. The dynamic PET imaging showed that [¹⁸F]45 was able to cross the blood–brain barrier, but non-specific uptake was observed, confirming the in vitro results. Conclusions: Although promising nanomolar affinity for the target, the new tracer showed mainly non-specific in vivo uptake in the rat brain, indicating that further pharmacomodulations on the azaindole series are required. Full article

Prostate-specific membrane antigen (PSMA) targeting agents have been the cornerstone of advanced prostate cancer (PCa) management in theranostics due to their high sensitivity for detecting and treating metastatic disease. However, approximately one-third of metastatic castration-resistant PCa (mCRPC) lesions may exhibit low or absent PSMA expression due to tumor heterogeneity, prior androgen deprivation therapy, or loss of androgen receptor expression, subsequently altering their response to PSMA-targeted therapy. The molecular and biological mechanisms underlying PSMA downregulation remain elusive but may include neuroendocrine differentiation or epithelial-to-mesenchymal transition (EMT). This review addresses this knowledge gap by examining recent preclinical and clinical evidence on novel radiotracers with the potential to provide alternative strategies beyond PSMA for imaging and treating PCa. The diagnostic performance and therapeutic potential of three emerging radiotracer classes are discussed, including gastrin-releasing peptide receptor (GRPR) ligands, androgen receptor (AR) ligands, and amino acid analogs. This article further highlights the complementary roles of these radiotracers along with their utility in specific patient populations, such as those with low prostate-specific antigen (PSA), biochemical recurrence (BCR), or confirmed PSMA-negative disease. For instance, GRPR-targeted radiotracers have achieved sensitivity of up to 88% and specificity of up to 90% for detecting primary tumors in PCa. The radiolabeled androgen agonist, fluorine-18 (¹⁸F)-fluoro-5α-dihydrotestosterone (FDHT), has demonstrated 98% true-positive rate in predicting lesions on positron emission tomography (PET) scans of mCRPC patients. On the other hand, the synthetic amino acid analog ¹⁸F-fluciclovine demonstrated a lesion detection rate of 84% for PSA levels at or above 5, and 62.5% for PSA levels ranging from 0.7 to less than 1. This review concludes with future directions on the paradigm of multi-tracer and dual-targeting strategies, which can effectively address challenges associated with PCa tumor heterogeneity and facilitate personalized approaches in theranostics. Full article

Despite technological progress, glioblastoma (GBM) continues to confer dismal prognoses. Modern neuroimaging methods are assuming an ever greater role in diagnosing and monitoring brain tumors. This review shows current neuroimaging approaches and systemic therapeutic strategies for glioblastoma, with a focus on emerging and innovative treatments. Advances in multiparametric magnetic resonance imaging—MRI (diffusion, perfusion, and spectroscopy) and novel positron emission tomography (PET) tracers, complemented by radiomics and artificial intelligence (AI), now refine tumor delineation, differentiate progression from treatment effects, and may help predict treatment responses. Maximal safe resection followed by chemoradiotherapy with temozolomide remains the standard, with the greatest benefit seen in O⁶-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumors. Bevacizumab and other targeted modalities offer mainly progression-free, not overall survival, gains. Immune checkpoint inhibitors (e.g., nivolumab) have not improved survival in unselected GBM, while early multi-antigen CAR-T (chimeric antigen receptor T-cell) strategies show preliminary bioactivity without established durability. While actionable alterations (NTRK fusions and BRAF V600E) justify selective targeted therapy trials, their definitive benefit in classical GBM is unproven. Future priorities include harmonized imaging molecular integration, AI-driven prognostic modeling, novel PET tracers, and strategies to breach or transiently open the blood–brain barrier to enhance drug delivery. Convergence of these domains may convert diagnostic precision into improved patient outcomes. Full article

Background: While prostate-specific membrane antigen (PSMA)-targeted imaging has revolutionized metastatic detection, unspecific bone uptake (UBU)—particularly in the ribs—is a common but diagnostically challenging finding in prostate cancer (PCa) patients. This review aims to synthesize current evidence on PSMA-avid rib lesions in PCa and to propose a structured approach for differentiating true metastases from benign mimics. Methods: A comprehensive literature search across PubMed, EMBASE, Scopus, and Web of Science identified relevant studies on PSMA imaging interpretation, tracer-specific patterns, rib lesion morphology, and clinical correlates. Data on uptake intensity, CT features, lesion number, location, tracer type, patient-specific risk factors, and follow-up behavior were extracted and analyzed. Results: Most solitary rib lesions are benign, particularly in low-risk patients or when located in the anterior/lateral arcs. Metastatic lesions are more likely to present as multiple foci, show cortical destruction on CT, exhibit high uptake intensity, and occur in patients with elevated PSA, high Gleason score, or ongoing androgen deprivation. ¹⁸F-PSMA-1007 is especially prone to UBU in the ribs compared to ⁶⁸Ga-PSMA-11. Based on these variables, we propose a clinical decision tree to guide interpretation of PSMA-avid rib lesions. Conclusions: Accurate interpretation of rib lesions on PSMA PET/CT requires a multimodal, context-sensitive approach. Our diagnostic decision tree guides precise differentiation of benign versus metastatic rib lesions, enhancing staging accuracy and clinical decision-making. Biomarker-guided therapies offer potential for personalized treatment, though rib-specific validation remains a critical need. Full article

Background/Objectives: The gastrin-releasing peptide receptor (GRPR) shows high-density expression in prostate cancer (PCa), especially in the early stages of the disease. The introduction of a safe radiotracer for assessing GRPR-expression in PCa may serve as an alternative or complementary tracer to PSMA-directed probes for patients with insufficient PSMA expression. In the present study, the tolerability and safety, biodistribution, and dosimetry of the new GRPR-targeting radiopeptide [^99mTc]Tc-DB8 were investigated for the first time in male PCa patients. A mass escalation study was performed, aiming to improve tumor-to-background contrast and, thereby, to enhance diagnostic accuracy. Methods: Sixteen male patients were enrolled in a single-center diagnostic open-label exploratory Phase I clinical trial. Patients were administered a single intravenous injection of 40, 80, or 120 µg of [^99mTc]Tc-DB8 peptide (n = 5–6) and underwent whole-body planar imaging (anterior and posterior) 2, 4, 6, and 24 h post-injection (pi) and SPECT-CT acquisition 2, 4, and 6 h pi. Results: Administration of [^99mTc]Tc-DB8 was well tolerated at all tested peptide masses. The effective dose did not differ significantly between the injected peptide mass and was 0.005 ± 0.003 mSv/MBq. High activity uptake was observed in the pancreas and kidneys, which 3-fold decreased with an increasing injected peptide mass from 40 to 120 µg. The activity uptake in primary tumors did not differ significantly between cohorts injected with different peptide masses [SUV_max 1.65–9.96]. The tumor-to-muscle ratios increased with time and were the highest for the cohort injected with 120 µg of peptide, 7.2 ± 3.1 (4.64-11-25) at 4 h pi. Conclusions: Single intravenous administration of [^99mTc]Tc-DB8, for visualization of GRPR expression in PCa using SPECT imaging was well tolerated in a peptide mass range of 40–120 µg. An injected peptide mass of 80–120 µg/patient and SPECT acquisition 2–4 h pi were found to be optimal for further clinical studies due to the significantly lower activity accumulation in the pancreas and kidneys. Full article

Lipid nanoparticles/liposomes (LNPs) represent a highly adaptable nanocarrier system that has gained significant traction in oncology for both therapeutic and diagnostic (theranostic) purposes. Their structural flexibility, biocompatibility, and capacity to encapsulate diverse therapeutic agents ranging from chemotherapeutics to nucleic acids and imaging tracers have enabled targeted cancer treatment with improved efficacy and reduced systemic toxicity. This review critically examines liposome-based platforms across a broad spectrum of cancers, including melanoma, lung, colorectal, liver, breast, ovarian, pancreatic, brain tumors, sarcoma, neuroblastoma, and leukemia. It outlines recent advances in ligand-mediated targeting, pH- and temperature-responsive release systems, and multifunctional LNPs capable of delivering combined therapeutic and imaging payloads. Moreover, the review discusses preclinical outcomes, current clinical trial status, and the challenges hindering clinical translation. By integrating recent innovations and emphasizing translational potential, this work highlights the pivotal role of LNPs in advancing precision cancer therapeutics and diagnostics. Full article

The subject of the research was a prototype two-row sprayer, equipped with a centrifugal fan and directed air-jet emission system, dedicated to the chemical protection of berry plantations, and, in particular, blackcurrants. The prototype was set up with two configurations: “offset”, in which the opposing air streams were “offset” by 0.5 m, and “face-to-face”, when they were positioned opposite each other. The field experiments were carried out on a blackcurrant plantation (Tisel cv.; bush spacing of 4.0 × 0.5 m; height 1.2 m; width 2.5 m). The spray deposition within the crop canopies as well as spray drift to the air and to the ground were assessed using the fluorescence method in order to compare the quality of treatments performed with the two-row sprayer and a conventional axial fan sprayer with radial air discharge system. Spray applications were performed at spray volume 300 L∙ha⁻¹ and working speed 6 km h⁻¹ by both sprayers. The plantation was sprayed with 0.25% water solution of a fluorescent tracer BF7G. The in-canopy spray deposit and spray drift were evaluated using artificial targets made of filter paper. Although directed air-jet sprayer in two configurations (“offset” and “face-to-face”) and conventional one produced similar deposits within the bushes, the spray loss from the directed air-jet sprayer was considerably lower (25.1–32.2%) than that from the conventional sprayer (76.9–81.8%) generating considerably greater airflow volume. Lower PPP losses mean lower environmental impact, which is in line with integrated plant protection. The research responds to numerous inquiries from sprayer manufacturers and blackcurrant growers regarding the most appropriate configuration of the air flow outlet planes. The results obtained will contribute to increasing the efficiency of spraying and facilitate the implementation of the European Green Deal and the achievement of the target of a 50% reduction in the use of plant protection products after 2030 in the EU. Full article

Senescence is a dynamic, multifaceted process implicated in tissue aging, organ dysfunction, and intricately associated with numerous chronic diseases. As senescent cells accumulate, they drive inflammation, fibrosis, and metabolic disruption through the senescence-associated secretory phenotype (SASP). Despite its clinical relevance, senescence remains challenging to detect non-invasively due to its heterogeneous nature and the lack of universal biomarkers. Recent advances in the development of specific imaging probes for positron emission tomography (PET) enable in vivo visualization of senescence-associated pathways across key organs, such as the lung, heart, kidney, and metabolic processes. For instance, [¹⁸F]FPyGal, a β-galactosidase-targeted tracer, has demonstrated selective accumulation in senescent cells in both preclinical and early clinical studies, while FAP-targeted radioligands are emerging as tools for imaging fibrotic remodeling in the lung, liver, kidney, and myocardium. This review examines a new generation of PET radioligands targeting hallmark features of senescence, with the potential to track and measure the process, the ability to be translated into clinical interventions for early diagnosis, and longitudinal monitoring of senescence-driven pathologies. By integrating organ-specific imaging biomarkers with molecular insights, PET probes are poised to transform our ability to manage and treat age-related diseases through personalized approaches. Full article

Spinal cord injury (SCI) often results in long-term locomotor impairments, and strategies to enhance functional recovery remain limited. While epidural electrical stimulation (EES) has shown clinical promise, our understanding of the mechanisms by which it improves function remains incomplete. Here, we use genetic tools in an animal model to perform neuromodulation and treadmill rehabilitation in a manner similar to EES, but with the benefit of the genetic tools and animal model allowing for targeted manipulation, precise quantification of the cells and circuits that were manipulated, and the gathering of extensive kinematic data. We used a viral construct that selectively transduces large diameter afferent fibers (LDAFs) with a designer receptor exclusively activated by a designer drug (hM3Dq DREADD; a chemogenetic construct) to increase the excitability of large fibers specifically, in the rat contusion SCI model. As changes in locomotion with afferent stimulation can be subtle, we carried out a detailed characterization of the kinematics of locomotor recovery over time. Adult Long-Evans rats received contusion injuries and direct intraganglionic injections containing AAV2-hSyn-hM3Dq-mCherry, a viral vector that has been shown to preferentially transduce LDAFs, or a control with tracer only (AAV2-hSyn-mCherry). These neurons then had their activity increased by application of the designer drug Clozapine-N-oxide (CNO), inducing tonic excitation during treadmill training in the recovery phase. Kinematic data were collected during treadmill locomotion across a range of speeds over nine weeks post-injury. Data were analyzed using a mixed effects model chosen from amongst several models using information criteria. That model included fixed effects for treatment (DREADDs vs. control injection), time (weeks post injury), and speed, with random intercepts for rat and time point nested within rat. Significant effects of treatment and treatment interactions were found in many parameters, with a sometimes complicated dependence on speed. Generally, DREADDs activation resulted in shorter stance duration, but less reduction in swing duration with speed, yielding lower duty factors. Interestingly, our finding of shorter stance durations with DREADDs activation mimics a past study in the hemi-section injury model, but other changes, including the variability of anterior superior iliac spine (ASIS) height, showed an opposite trend. These may reflect differences in injury severity and laterality (i.e., in the hemi-section injury the contralateral limb is expected to be largely functional). Furthermore, as with that study, withdrawal of DREADDs activation in week seven did not cause significant changes in kinematics, suggesting that activation may have dwindling effects at this later stage. This study highlights the utility of high-resolution kinematics for detecting subtle changes during recovery, and will enable the refinement of neuromechanical models that predict how locomotion changes with afferent neuromodulation, injury, and recovery, suggesting new directions for treatment of SCI. Full article

Glycosaminoglycans (GAGs) are part of the extracellular matrix (ECM) and play a major role in maintaining their physiological function. During pathological processes, the ECM is remodeled and its GAG composition changes. Hyaluronic acid (HA) is one of the GAGs that plays an important role in pathological processes such as inflammation and cancer and is therefore an interesting target for imaging. To provide iron oxide nanoparticles (IONP) that bind to hyaluronic acid (HA) as specific probes for molecular imaging, a peptide with high affinity for HA was covalently bound to the surface of commercial IONP (synomag^®-D, NH2) leading to hyaluronic acid-specific iron oxide nanoparticles (HAIONPs). Affinity measurements using a quartz crystal microbalance (QCM) showed a very high affinity of HAIONP to HA, but not to the control chondroitin sulfate (CS). HAIONPs exhibit a very high magnetic particle spectroscopy (MPS) signal amplitude, which predestines them as HA-selective tracers for magnetic particle imaging (MPI). The high relaxivity coefficient r₂ also makes HAIONP suitable for magnetic resonance imaging (MRI) applications. HAIONP therefore offers excellent prerequisites for further development as a probe for the specific quantitative imaging of the HA content of the ECM in pathological areas. Full article

The development of positron emission tomography (PET) tracers targeting α-synuclein (α-syn) aggregates is critical for the early diagnosis, differential classification, and therapeutic monitoring of synucleinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Despite recent advances, challenges including the low abundance of α-syn aggregates (10–50× lower than amyloid-beta (Aβ) or Tau), structural heterogeneity (e.g., flat fibrils in PD vs. cylindrical forms in DLB), co-pathology with Aβ/Tau, and poor metabolic stability have hindered PET tracer development for this target. To optimize our previously reported pyridothiophene-based radiotracer, [¹⁸F]asyn-44, we present the synthesis and evaluation of novel S,N-heterocyclic scaffold derivatives for α-syn. A library of 49 compounds was synthesized, with 8 potent derivatives (LMD-006, LMD-022, LMD-029, LMD-044, LMD-045, LMD-046, LMD-051, and LMD-052) demonstrating equilibrium inhibition constants (K_i) of 6–16 nM in PD brain homogenates, all of which are amenable for radiolabeling with fluorine-18. This work advances the molecular toolkit for synucleinopathies and provides a roadmap for overcoming barriers in PET tracer development, with lead compounds that can be considered for biomarker-guided clinical trials and targeted therapies. Full article

The highly heterogeneous and invasive nature characteristic of high-grade gliomas (HGG) has historically limited the efficacy of standard-of-care approaches, resulting in poor prognosis and treatment outcomes. Novel immunotherapies have shown remarkable potential to promote antitumoral immune responses and allow for long-term tumor remission. However, the complexity of the HGG tumor microenvironment and the dynamic immunological changes associated with immunotherapy response can limit the diagnostic utility of conventional magnetic resonance imaging (MRI) and positron emission tomography (PET) approaches. Consequently, distinguishing true tumor progression from immunotherapy-related effects often requires prolonged clinical follow-up over several months. To address this, novel quantitative MRI and PET-based approaches are being evaluated in preclinical studies and clinical trials. These advanced imaging methods target key biological features of the tumor microenvironment, including vascularity, cellularity, intratumoral habitats, tracer pharmacokinetics and immune infiltration, and can provide metrics to stratify patient response at earlier timepoints to support clinical decision making and improve treatment outcomes. This review highlights key HGG biological characteristics, describes standard-of-care and emerging therapeutic strategies, and discusses both conventional and advanced imaging methods to characterize immunotherapeutic responses. Full article

The present study develops and optimizes a targeted chromatographic method coupled with mass spectrometry, employing design of experiments, for the determination of several emerging contaminants in environmental waters. Their widespread presence poses environmental and health risks due to their pseudo-persistence and unknown long-term effects. Therefore, sensitive and selective analytical methods are essential for their reliable environmental monitoring. This work focuses on 40 organic micro-contaminants with a wide range of polarities, including drugs, pesticides and UV-filters. Chromatographic separation was performed on a pentafluorophenyl column, and a Face-Centered Design was applied for multivariate optimization. Mobile phase flow and temperature were chosen as the study factors, and retention time and peak width as the responses, as indicators of analytical performance. Two optimized runs (for positive and negative electrospray ionization modes) were obtained, enabling the analysis of all 40 analytes in a total of 29 min. The final method was successfully applied to seawater samples from different sites of the Genoa harbor area. Several analytes were detected and quantified, down to the ng L⁻¹ level, with tracers and pharmaceuticals showing the highest concentrations. The method demonstrated satisfactory accuracy, precision and specificity and is suitable for routine monitoring of a broad range of emerging contaminants in seawater. Full article

Oral fluid sampling is a well-established, non-invasive method for disease surveillance in growing pigs; however, its application in group-housed gestating sows is under-researched. This study (1) characterized sow behaviors associated with oral fluid sampling and (2) documented the transfer of an environmental target into pen-based oral fluid samples. Field observations were conducted on a commercial sow farm in 12 pens of gestating sows sorted by parity (gilts, parity one, and multiparous sows). Sow oral fluid sampling behaviors were quantified by recording interactions with rope samplers using video cameras and then analyzing the recorded footage. All oral fluid sampling attempts were successful. Unlike growing pigs, experience with rope samplers (“training”) did not increase sow participation, but participation in oral fluid collection did increase as sampling time increased. The transfer of environmental components into oral fluid samples was demonstrated by introducing a fluorescent tracer into the pen and then detecting specific fluorescence in the samples (8 of 12 pens). These findings support the implementation of oral fluid sampling in group-housed sows and provide practical recommendations for optimizing surveillance protocols, including extended sampling times and use of at least two ropes per pen. Full article