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Search Results (258)

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Keywords = radiotracer development

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13 pages, 2172 KB  
Article
Bridging Research and Clinical Practice: Automated [68Ga]Ga-FAPi-46 Synthesis and Quality Control for Oncological PET Imaging
by Caiubi Rodrigues de Paula Santos, Luciana Malavolta, Jorge Mejia, Leonardo Lima Fuscaldi, Lilian Yuri Itaya Yamaga and Marycel Figols de Barboza
Pharmaceuticals 2026, 19(4), 594; https://doi.org/10.3390/ph19040594 - 8 Apr 2026
Viewed by 444
Abstract
Background/Objectives: Fibroblast activation protein (FAP) has emerged as a promising target for oncologic molecular imaging due to its high expression in cancer-associated fibroblasts and low presence in healthy tissues. Among available FAP ligands, [68Ga]Ga-FAPi-46 has shown rapid tumor accumulation, low background [...] Read more.
Background/Objectives: Fibroblast activation protein (FAP) has emerged as a promising target for oncologic molecular imaging due to its high expression in cancer-associated fibroblasts and low presence in healthy tissues. Among available FAP ligands, [68Ga]Ga-FAPi-46 has shown rapid tumor accumulation, low background uptake, and broad tumor applicability. This study reports the successful translation of [68Ga]Ga-FAPi-46 from preclinical development to routine clinical radiopharmacy practice, detailing automated synthesis, quality control performance, radiochemical stability, and the first clinical imaging results. Methods: Automated radiolabeling of FAPi-46 with gallium-68 was performed using a synthesis module. Quality control included radiochemical purity assessments by iTLC, SPE, and RP-HPLC (pH, appearance, endotoxin levels, and membrane integrity testing). Radiochemical stability was evaluated in saline (up to 6 h) and human serum (up to 90 min). In vitro characterization included the partition coefficient and serum protein binding determination. A clinical evaluation was conducted in a woman with newly diagnosed lung adenocarcinoma who underwent both [18F]FDG PET/CT and [68Ga]Ga-FAPi-46 PET/CT. Results: Automated synthesis of [68Ga]Ga-FAPi-46 achieved a high radiochemical yield (87.9 ± 1.3%) and radiochemical purity greater than 98%. All batches met release specifications for sterility, apyrogenicity, and physicochemical parameters. The radiotracer demonstrated high stability in saline and human serum, with radiochemical purity consistently above 95% at all evaluated time points. The compound showed a hydrophilic profile (LogP = −3.32 ± 0.14) and 40–60% serum protein binding. Clinically, [68Ga]Ga-FAPi-46 PET/CT provided superior lesion delineation compared to [18F]FDG, revealing additional mediastinal, supraclavicular, and brain metastases. Conclusions: [68Ga]Ga-FAPi-46 can be reliably synthesized using automated procedures under routine radiopharmacy conditions, meeting regulatory quality standards and demonstrating excellent stability. Its enhanced lesion detectability compared with [18F]FDG in the first patient case supports its potential value for oncological staging and clinical implementation. Full article
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15 pages, 751 KB  
Review
Positron Emission Tomography/Computed Tomography in Bladder Cancer: The Role of [18F]FDG and Non-FDG Radiotracers
by Hanna Falińska, Ewa Witkowska-Patena, Karolina Krzyżanowska and Mirosław Dziuk
Medicina 2026, 62(4), 703; https://doi.org/10.3390/medicina62040703 - 7 Apr 2026
Viewed by 338
Abstract
Background and Objectives: Bladder cancer is one of the most common malignancies of the urinary tract and poses a significant clinical challenge due to its biological heterogeneity and high rates of recurrence and progression. Urothelial carcinoma represents the predominant histological subtype, ranging [...] Read more.
Background and Objectives: Bladder cancer is one of the most common malignancies of the urinary tract and poses a significant clinical challenge due to its biological heterogeneity and high rates of recurrence and progression. Urothelial carcinoma represents the predominant histological subtype, ranging from non-muscle-invasive disease with relatively favorable outcomes to aggressive muscle-invasive and metastatic forms associated with poor prognosis. Accurate diagnosis, staging, prognostic stratification, and assessment of treatment response are therefore essential for optimal patient management. The objective of this review is to summarize and critically evaluate the current evidence on the role of positron emission tomography/computed tomography (PET/CT) in bladder cancer, with particular emphasis on [18F]FDG PET/CT and non-FDG radiotracers. Materials and Methods: A narrative review of the available literature was performed, focusing on clinical studies, review articles, and guideline documents addressing the use of PET/CT in bladder cancer. The literature search included articles published between 2000 and 2025, while earlier landmark studies were selectively included if considered historically important for understanding the development of PET/CT imaging in bladder cancer. The initial search yielded over 500 records; after screening titles and abstracts, more than 100 articles were selected for full-text evaluation. The analyzed evidence encompasses the clinical applications of [18F]FDG PET/CT and alternative radiotracers, including choline-, acetate-, methionine-, and sodium fluoride-based tracers, and fibroblast activation protein inhibitors (FAPI), across different stages of disease and clinical settings. Results: Conventional imaging modalities, such as computed tomography and magnetic resonance imaging, provide important anatomical information but remain limited in the evaluation of lymph node involvement, early metastatic disease, treatment response, and disease recurrence. Despite limitations related to physiological urinary excretion, [18F]FDG PET/CT has demonstrated clinical value in selected scenarios, particularly for staging, prognostic assessment, detection of recurrence, and response evaluation. To overcome FDG-related constraints, several non-FDG radiotracers have been investigated. Among these, FAPI PET/CT has emerged as a promising modality due to its ability to target the tumor stroma, potentially improving lesion detectability and tumor-to-background contrast. Conclusions: This review summarizes and critically evaluates current evidence on the role of PET/CT in bladder cancer, with a focus on [18F]FDG PET/CT and non-FDG radiotracers. The discussed studies highlight their applications in primary diagnosis, staging, prognostic assessment, detection of recurrence, and evaluation of treatment response, as well as their respective advantages and limitations. Furthermore, potential future directions for PET/CT imaging in clinical practice are outlined, emphasizing the need for further research to clarify the optimal use of established and emerging radiotracers. Full article
(This article belongs to the Special Issue Interventional Radiology and Imaging in Cancer Diagnosis)
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20 pages, 1982 KB  
Article
Revisiting the F3 Peptide: In Vitro Investigations of C- and N-Terminally Modified Peptide Conjugates for Radiotracer Development
by Maximilian Anderla, Marlene Grillmayr, Katharina Huemer and Thomas L. Mindt
Pharmaceuticals 2026, 19(4), 558; https://doi.org/10.3390/ph19040558 - 31 Mar 2026
Viewed by 429
Abstract
Background/Objectives: The F3 peptide, a tumor-homing peptide known to bind cell-surface nucleolin, is frequently employed as a targeting vector in cancer research. However, the impact of the modification site on its cellular binding properties has not been investigated yet. In this work, [...] Read more.
Background/Objectives: The F3 peptide, a tumor-homing peptide known to bind cell-surface nucleolin, is frequently employed as a targeting vector in cancer research. However, the impact of the modification site on its cellular binding properties has not been investigated yet. In this work, we aimed to design an improved F3-based radioconjugate by identifying the optimal conjugation site and establishing a protocol for its biological evaluation in vitro. To achieve this, we compared F3 peptide derivatives modified at their N- or C-termini with DOTA for complexation of indium-111 (111In) for SPECT or Auger electron therapy or a fluorophore (FITC) for optical imaging. Methods: N-and C-terminal DOTA-modified F3 peptides were radiolabeled with indium-111 and compared for their in vitro stability in different physiologically relevant media. Suitable nucleolin-positive cell lines for further in vitro studies were identified by confocal microscopy of a FITC-labeled F3 peptide derivative. The radioconjugates were then investigated on MDA-MB-231 (breast cancer) and PC-3 (prostate cancer) cells for nucleolin-specific cell binding and uptake, and several parameters of the in vitro assays were varied to establish a suitable protocol. Results: In general, in vitro assays with F3 peptide conjugates are challenging, as the outcome depends on a number of experimental parameters, leading, in some cases, to varying results. In particular, the presence of Ca2+ and Mg2+ had a decisive impact on the results, likely because the metal ions compete with the binding of F3 conjugates to nucleolin. The C-terminal modified, 111In-labeled F3 radioconjugate performed better than the N-terminal modified analog. While several parameters of the in vitro experiments were optimized, the overall cell uptake in vitro of radioactivity was still low (<2% of applied radioactivity). Conclusions: A standardized in vitro protocol for evaluating F3 peptide conjugates on cancer cells was established, revealing that the C-terminus is the preferred site for modification. Because the cellular uptake of the radiotracer was shown to likely not be sufficient for radiotracer development, further studies on the optimization of the F3 peptide conjugates, including structural modifications, are required. Full article
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21 pages, 4034 KB  
Article
Developability Evaluation of Single-Domain Antibody-Chelator Conjugates for Diagnostic Radiotracers
by Philipp D. Kaiser, Simon Straß, Sandra Maier, Evgenia Herbold, Bjoern Traenkle and Anne Zeck
Antibodies 2026, 15(2), 22; https://doi.org/10.3390/antib15020022 - 3 Mar 2026
Viewed by 709
Abstract
Background/Objectives: Developability assessment is a critical step in advancing antibody-based molecules toward clinical application. This evaluation typically begins during clinical candidate selection and continues throughout all modifications of the molecule during development. It is guided by the target product profile, which includes [...] Read more.
Background/Objectives: Developability assessment is a critical step in advancing antibody-based molecules toward clinical application. This evaluation typically begins during clinical candidate selection and continues throughout all modifications of the molecule during development. It is guided by the target product profile, which includes the intended administration route and regimen, formulation parameters, and process conditions encountered during manufacturing, storage, and delivery. While developability testing is well established for conventional therapeutic antibodies, strategies for assessing single-domain antibodies (sdAbs) and their conjugates remain underexplored. Here, we present a strategy to test the developability of sdAbs as a case study for two clinical candidates intended as precursors for the production of diagnostic tracers for clinical imaging. Methods: Assays were developed to evaluate chemical and thermodynamic stability, target binding affinity and capacity, and chelation efficiency (“chelatability”). Accelerated stability studies were conducted for both unconjugated sdAbs and their chelator conjugated forms following incubation at two pH conditions, at multiple time points, and after twelve freeze–thaw cycles to simulate process conditions and long-term storage. Analytical assays were applied stepwise in a hierarchical approach to minimize experimental effort and material consumption. Candidates exhibiting critical developability features were selectively addressed by assays with increasing precision. Results: A tailored panel of analytical assays optimized for low molecular weight proteins was established and applied to the two clinical candidates, identifying instability hotspots as well as potential mitigation strategies. Successful engineering of a candidate with an initially critical developability profile was achieved. Conclusions: This study demonstrates the implementation of a structured developability assessment strategy for sdAb conjugates. The approach integrates physicochemical and functional stability evaluations, supporting robust candidate selection, formulation development, and method optimization for this class of molecules. Full article
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25 pages, 2697 KB  
Review
Tumour Microenvironment-Informed Radiotheranostics: Why and How Nuclear Medicine Could Advance Precision Oncology in the Decade Ahead
by Kalyani Pandya, Zhaoguo Lin, Magdalena Wadsak, Jiahui Wang, Kuangyu Shi and Robert Seifert
Pharmaceuticals 2026, 19(3), 382; https://doi.org/10.3390/ph19030382 - 27 Feb 2026
Viewed by 800
Abstract
Despite significant progress in targeted cancer therapies and conventional imaging methodologies, the effective detection and treatment of solid tumours remain a major clinical challenge. This is thought to be caused by the complexity and heterogeneity found in the tumour microenvironment (TME), which significantly [...] Read more.
Despite significant progress in targeted cancer therapies and conventional imaging methodologies, the effective detection and treatment of solid tumours remain a major clinical challenge. This is thought to be caused by the complexity and heterogeneity found in the tumour microenvironment (TME), which significantly effects drug delivery and therapeutic response. Different levels of fibrosis, varying immune-cell infiltration, and disorganized vasculature form barriers for therapeutic approaches. However, in the next decade, radiotheranostics, defined here as the combined use of matched diagnostic and therapeutic radiopharmaceuticals, could present a targeted and flexible strategy for addressing some of the challenges caused by the TME. By combining molecular imaging with therapeutic delivery, it enables the in vivo visualization of TME features and the selective treatment of tumour and stromal compartments. This provides the unique opportunity to target tumour regions resistant to conventional therapies, including those shaped by (extracellular matrix) ECM stiffness, immune infiltration, or hypoxia. However, new strategies are needed to identify targets and evaluate their efficacy for more precise therapies. In this review, we will discuss why radiotheranostics is an ideal field for advancing the therapeutic approaches to solid tumours by incorporating the growing understanding of the TME. We will discuss how key microenvironmental features affect radiotracer distribution and treatment outcomes. We will highlight emerging tools including ECM- and immune-targeted imaging, patient-derived organoids, and organ-on-chip models which will be instrumental in developing physiologically relevant radiopharmaceutical therapies. Finally, we will discuss how spatial/single-cell transcriptomic approaches can support target discovery and allow for patient outcome assessment, with the aim of integrating microenvironment-aware insights into the development of novel radiotheranostic agents. Full article
(This article belongs to the Collection Will (Radio)Theranostics Hold Up in the 21st Century—and Why?)
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18 pages, 2428 KB  
Article
Streamlined Radiosynthesis of [18F]Fluproxadine (AF78): An Unprotected Guanidine Precursor Enables Efficient One-Step, Automation-Ready Labeling for Clinical Use
by Xinyu Chen, Kaito Ohta, Hiroyuki Kimura, Yusuke Yagi, Takanori Sasaki, Naoko Nose, Masaru Akehi, Tomohiko Yamane, Rudolf A. Werner and Takahiro Higuchi
Pharmaceutics 2026, 18(1), 123; https://doi.org/10.3390/pharmaceutics18010123 - 19 Jan 2026
Viewed by 558
Abstract
Background/Objectives: [18F]Fluproxadine (formerly [18F]AF78) is a PET radiotracer targeting the norepinephrine transporter (NET) with potential applications in cardiac, neurological, and oncological imaging. Its guanidine moiety, while essential for NET binding, presents major radiosynthetic challenges due to high basicity and [...] Read more.
Background/Objectives: [18F]Fluproxadine (formerly [18F]AF78) is a PET radiotracer targeting the norepinephrine transporter (NET) with potential applications in cardiac, neurological, and oncological imaging. Its guanidine moiety, while essential for NET binding, presents major radiosynthetic challenges due to high basicity and the harsh deprotection conditions required for protected precursors. Previous methods relied on multistep procedures, strong acids, and complex purification, limiting clinical translation. This study aimed to develop a practical one-step radiosynthesis suitable for routine and automated production. Methods: A direct SN2-type nucleophilic [18F]fluorination was performed using an unprotected guanidine precursor to eliminate deprotection steps. Reaction parameters, including the base system, solvent composition, precursor concentration, and temperature, were optimized under conventional and microwave heating. Radiochemical conversion (RCC) and operational robustness were evaluated, and purification strategies were assessed for automation compatibility. Results: Direct [18F]fluorination using the unprotected precursor reduced the total synthesis time to 60–70 min. Optimal conditions employed a tert-butanol/acetonitrile (4:1) solvent system with K2CO3/Kryptofix222, affording RCC up to 33% under conventional heating. Microwave irradiation further improved efficiency, achieving RCC of up to 64% within 1.5 min at 140 °C. The method showed broad tolerance to variations in the base molar ratio and precursor concentration and enabled isocratic HPLC purification. Conclusions: This one-step radiosynthesis overcomes longstanding challenges in [18F]fluproxadine production by eliminating harsh deprotection and enabling high-yield, automation-ready synthesis, thereby improving clinical feasibility. Full article
(This article belongs to the Section Clinical Pharmaceutics)
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15 pages, 5553 KB  
Article
Animal Models of Alzheimer’s Disease Evaluated with [11C]Pittsburg Compound B
by Santiago Burgos-Puentes, Arturo Avendaño-Estrada, Marquiza Sablón-Carrazana, Eleazar Ramírez-Hernández, Andrea Granados-Juárez, Gerardo Bernabé Ramírez-Rodríguez, Marco Meraz-Ríos, Hilda Martínez-Coria and Miguel A. Ávila-Rodríguez
Life 2026, 16(1), 123; https://doi.org/10.3390/life16010123 - 14 Jan 2026
Cited by 1 | Viewed by 643
Abstract
Several animal models of Alzheimer’s disease have been developed and tested for diagnostic and treatment purposes. [11C]PIB is the gold-standard radiotracer for the detection of Aβ plaque deposits, a hallmark of the disease. This study aimed to evaluate the in vivo [...] Read more.
Several animal models of Alzheimer’s disease have been developed and tested for diagnostic and treatment purposes. [11C]PIB is the gold-standard radiotracer for the detection of Aβ plaque deposits, a hallmark of the disease. This study aimed to evaluate the in vivo detection of Aβ plaques using [11C]PIB microPET imaging across different animal models of Alzheimer’s disease. The study included 3xTg-AD transgenic mice, TgF344-AD transgenic rats and Aβ injection-based rat model. The results showed an age-related increase in [11C]PIB uptake in 3xTg-AD mice, particularly in the midbrain and thalamus. In TgF344-AD rats, differences were also observed compared to WT controls, with the highest values observed in the hippocampus and cortex. In the injection-based model, inoculated rats showed greater uptake in the injection site than SHAM animals. Across all microPET studies, [11C]PIB uptake was consistently higher in females than in their male counterparts. These findings support the value of transgenic and Aβ injection-based models in preclinical research on Aβ plaque deposition and highlight the importance of considering species, model type, sex, and age in experimental design. Full article
(This article belongs to the Special Issue Advances in Medical Imaging of Animal Models for Human Diseases)
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21 pages, 687 KB  
Review
Radiolabelled FAPI Radiotracers in Oncology: A Comprehensive Review of Current Diagnostic and Emerging Therapeutic Applications
by Jolanta Czuczejko, Bogdan Małkowski, Jarosław Nuszkiewicz, Iga Hołyńska-Iwan, Paweł Waśniowski, Katarzyna Mądra-Gackowska, Wiktor Dróżdż and Karolina Szewczyk-Golec
Pharmaceuticals 2026, 19(1), 89; https://doi.org/10.3390/ph19010089 - 2 Jan 2026
Cited by 1 | Viewed by 1590
Abstract
Background/Objectives: Fibroblast activation protein (FAP), which is abundantly expressed in cancer-associated fibroblasts (CAFs) across various epithelial malignancies, has emerged as a promising target for molecular imaging and radionuclide therapy. Although several reviews have addressed FAP-targeted diagnostics, a comprehensive synthesis integrating molecular biology, [...] Read more.
Background/Objectives: Fibroblast activation protein (FAP), which is abundantly expressed in cancer-associated fibroblasts (CAFs) across various epithelial malignancies, has emerged as a promising target for molecular imaging and radionuclide therapy. Although several reviews have addressed FAP-targeted diagnostics, a comprehensive synthesis integrating molecular biology, diagnostic performance, and early therapeutic development remains limited. This review summarises the current evidence on radionuclide-labelled FAP inhibitors (FAPIs), with particular emphasis on their diagnostic utility, emerging therapeutic applications, and the structural features that shape their biological behaviour. Methods: A structured literature search was conducted across PubMed, Scopus, and Web of Science, focusing on FAPI-based imaging and therapy. Results: Diagnostic studies consistently demonstrate high tumour-to-background contrast for [68Ga]Ga and [18F]-labelled FAPI radiotracers, particularly in tumours with prominent stromal components such as pancreatic, colorectal, breast, and head and neck cancers. FAPI PET/CT often surpasses [18F]FDG in lesion conspicuity in the brain, liver, and peritoneum. Therapeutic evidence shows encouraging tumour retention and safety profiles for agents such as [177Lu]Lu-FAP-2286 and [90Y]Y-FAPI-46, while α-emitting radiotracers (e.g., [225Ac]Ac-FAPI-04) demonstrate potent antitumor effects in preclinical models. Conclusions: Radiolabelled FAPI radiotracers hold significant potential as dual diagnostic and therapeutic agents, particularly for desmoplastic tumours with high CAF content. Nonetheless, clinical evidence remains in its early stages, and substantial questions persist regarding dosimetry, intertumoral variability in FAP expression, and optimal ligand selection for therapy. Continued development of next-generation FAPI constructs, along with well-designed prospective trials, will be crucial in defining the future role of FAPI-based theranostics in oncology. Full article
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22 pages, 4931 KB  
Systematic Review
Advancements in Renal Imaging: A Comprehensive Systematic Review of PET Probes for Enhanced GFR and Renal Perfusion Assessment
by Marwah Abdulrahman, Ahmed Saad Abdlkadir, Serin Moghrabi, Salem Alyazjeen, Soud Al-Qasem, Deya’ Aldeen Sulaiman Sweedat, Saad Ruzzeh, Dragi Stanimirović, Michael C. Kreissl, Hongcheng Shi, Mike Sathekge and Akram Al-Ibraheem
Diagnostics 2025, 15(24), 3209; https://doi.org/10.3390/diagnostics15243209 - 15 Dec 2025
Viewed by 1310
Abstract
Glomerular filtration rate (GFR) is a key indicator of renal function. Traditional methods for GFR measurement have limitations including invasiveness, low spatial resolution, and lengthy protocols. Positron emission tomography (PET) radiotracers have emerged as promising tools for non-invasive, accurate, and dynamic renal function [...] Read more.
Glomerular filtration rate (GFR) is a key indicator of renal function. Traditional methods for GFR measurement have limitations including invasiveness, low spatial resolution, and lengthy protocols. Positron emission tomography (PET) radiotracers have emerged as promising tools for non-invasive, accurate, and dynamic renal function assessment. Objectives: This systematic literature review evaluates the clinical utility, and current evidence surrounding PET radiotracers used for GFR measurement in humans, emphasizing advances over conventional renal imaging modalities. Methods: A systematic literature search was conducted in PubMed, Web of Science, and Scopus, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, from database inception to November 2024. The search identified studies evaluating PET-based measurement of glomerular filtration rate (GFR) and renal perfusion. Inclusion criteria encompassed human studies using PET radiotracers (e.g., 68Ga, 18F) with comparisons to reference standards (estimated GFR or serum creatinine). Two authors independently screened titles/abstracts, extracted data, and assessed bias using Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2). Exclusions included animal studies, reviews, and non-English articles. Results: Eleven studies met inclusion criteria, with 68Ga-EDTA showing the highest validation against reference standards such as 51Cr-EDTA plasma clearance, demonstrating strong correlation. PET imaging offered superior spatial–temporal resolution, enabling accurate split renal function assessment and quantitative analysis of both filtration and perfusion. 68Ga-somatostatin analogues exhibited moderate correlations between renal SUV and estimated GFR, with post-PRRT uptake changes indicating early nephrotoxicity. Among novel tracers, 68Ga-FAPI showed a strong inverse SUV–GFR relationship, reflecting renal fibrosis and suggesting potential as a chronic kidney disease (CKD) biomarker but requires further clinical validation. Limitations across studies include small sample sizes, retrospective designs, and variability in reference standards. Conclusions: PET radiotracers, particularly 68Ga-EDTA, represent a significant advancement for non-invasive, quantitative GFR measurement with improved precision and renal anatomical detail compared to traditional methods. Future prospective, large-scale human studies with standardized protocols are needed to establish these PET tracers as routine clinical tools in nephrology. Integration of hybrid PET/MRI and novel tracer development may further enhance renal diagnostic capabilities. Full article
(This article belongs to the Special Issue Applications of PET/CT in Clinical Diagnostics)
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23 pages, 1636 KB  
Review
Nuclear Medicine Imaging Biomarkers in Parkinson’s Disease: Past, Present, and Future Directions
by Anna Lisa Martini, Stelvio Sestini, Dinahlee Saturnino Guarino and Paola Feraco
Med. Sci. 2025, 13(4), 308; https://doi.org/10.3390/medsci13040308 - 7 Dec 2025
Viewed by 1848
Abstract
Parkinson’s disease (PD) is a multifaceted neurodegenerative disorder characterized by dopaminergic neuronal loss and widespread α-synuclein pathology. Nuclear medicine imaging offers essential in vivo tools for early diagnosis, differential assessment, and monitoring disease progression. This review summarizes key PET and SPECT radiotracers targeting [...] Read more.
Parkinson’s disease (PD) is a multifaceted neurodegenerative disorder characterized by dopaminergic neuronal loss and widespread α-synuclein pathology. Nuclear medicine imaging offers essential in vivo tools for early diagnosis, differential assessment, and monitoring disease progression. This review summarizes key PET and SPECT radiotracers targeting dopaminergic synthesis and transport, vesicular storage, post-synaptic receptors, neuroinflammation, and protein aggregation, highlighting their roles in clinical evaluation and phenotyping. Clinically, these modalities support earlier recognition of PD, distinction from atypical parkinsonian syndromes, and assessment of non-motor involvement. Future directions include the development of selective α-synuclein tracers and multimodal imaging strategies to refine prodromal detection and guide personalized therapeutic interventions. Full article
(This article belongs to the Collection Advances in the Pathogenesis of Neurodegenerative Diseases)
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18 pages, 2608 KB  
Article
Toward Brain NaV1.8 Imaging with [11C]Suzetrigine
by Ramya Tokala, Torben D. Pearson, Braeden A. Mair, Sarah Bricault, Rachel Wallace, Hsiao-Ying Wey, Jacob M. Hooker and So Jeong Lee
Pharmaceuticals 2025, 18(12), 1816; https://doi.org/10.3390/ph18121816 - 28 Nov 2025
Viewed by 1581
Abstract
Background/Objective: Acute and chronic pain affect millions of individuals, yet there are currently no molecular imaging tools to directly assess pain-related mechanisms in the central nervous system (CNS). The voltage-gated sodium channel NaV1.8 plays a pivotal role in neuropathic pain by [...] Read more.
Background/Objective: Acute and chronic pain affect millions of individuals, yet there are currently no molecular imaging tools to directly assess pain-related mechanisms in the central nervous system (CNS). The voltage-gated sodium channel NaV1.8 plays a pivotal role in neuropathic pain by increasing the excitability of nociceptive neurons following nerve injury or inflammation. In this work, we aimed to develop a novel positron emission tomography (PET) imaging probe for NaV1.8 to facilitate noninvasive quantification of this target in the CNS and thereby advance our understanding of pain neurobiology. Methods: We selected the compound suzetrigine, a U.S. FDA-approved, highly selective non-opioid NaV1.8 inhibitor, as the first candidate for a NaV1.8-targeted PET tracer. The compound was first assessed using in silico docking and CNS multiparameter optimization (MPO) analysis to evaluate target binding and predicted brain penetrability. Radiolabeling was accomplished by O-methylation with [11C]methyl iodide to yield [11C]suzetrigine without structural modification. The tracer was then evaluated using in vitro binding assays, including autoradiography and saturation binding on rat brain tissues, to determine binding parameters (KD, Bmax), and using in vivo PET imaging in rats to assess brain uptake, time–activity curves (TACs), and tracer behavior under baseline and pretreatment conditions. Pretreatment was performed with unlabeled suzetrigine, the P-glycoprotein (P-gp) inhibitor verapamil, and the heterologous NaV1.8 inhibitor A-803467. Results: In silico docking demonstrated favorable binding of suzetrigine to the NaV1.8 active site, and the calculated CNS MPO score (>3.5) suggested adequate brain penetration. Radiochemical synthesis of [11C]suzetrigine via O-methylation yielded a high decay-corrected radiochemical yield (19.2 ± 2.7%, n = 3), excellent purity (>98%, n = 3), and moderate molar activity (62.9 ± 51.8 MBq/nmol, n = 3). Autoradiography on rat brain tissue confirmed saturable and selective binding of [11C]suzetrigine to NaV1.8. Saturation binding assays revealed a Bmax = 93 fmol/mg and a KD = 0.1 nM, supporting the imageability of NaV1.8 in the brain using this tracer. In vivo PET imaging in rats demonstrated rapid and sufficient brain uptake but revealed unexpected tracer behavior: signal intensity markedly increased following pretreatment with either unlabeled suzetrigine or the P-gp inhibitor verapamil, and showed a slight increase after pretreatment with the heterologous NaV1.8 inhibitor A-803467. Detailed analysis of PET images, TACs, and normalized area-under-curve (AUC) values indicated that these atypical uptake patterns were primarily attributable to P-gp-mediated effects, although additional factors may also contribute. Conclusions: [11C]Suzetrigine exhibits high affinity, good brain uptake, and selective target engagement in vitro, supporting its potential as a first-in-class NaV1.8-PET tracer. However, in vivo performance is confounded by P-gp-mediated efflux and possibly other mechanisms that limit accurate quantification of NaV1.8 in the living brain. These findings underscore the critical role of efflux transporters in CNS radiotracer development and highlight the need for design strategies that mitigate P-gp interaction when targeting ion channels in the brain. Future studies will include imaging under constant P-gp inhibition, arterial blood sampling for radiometabolite analysis and full kinetic modeling, and evaluation in non-human primates to assess translational feasibility. Full article
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28 pages, 1127 KB  
Review
A Full-Spectrum Evaluation of Sigma-1 Receptor (S1R) Positron Emission Tomography (PET) Radioligands from Binding Affinity to Clinical Imaging
by Francesco Mastropasqua, Friedrich-Alexander Ludwig and Carmen Abate
Molecules 2025, 30(21), 4296; https://doi.org/10.3390/molecules30214296 - 5 Nov 2025
Cited by 2 | Viewed by 1779
Abstract
Several pieces of evidence have demonstrated the sigma-1 receptor (S1R) as a druggable protein with important therapeutic potentials, including neurodegeneration, cancer, and neuropathic pain. The density of S1R is altered in pathological processes so that its imaging is under study for diagnostic purposes. [...] Read more.
Several pieces of evidence have demonstrated the sigma-1 receptor (S1R) as a druggable protein with important therapeutic potentials, including neurodegeneration, cancer, and neuropathic pain. The density of S1R is altered in pathological processes so that its imaging is under study for diagnostic purposes. Thus, research has been focused on the development of S1R positron emission tomography (PET) radioligands, not only as diagnostic tools but also as powerful means to assist in the drug-development process. Herein, we comprehensively review the most important S1R PET radiotracers belonging to different classes that have been developed in the last two decades. Starting from the structural modifications impacting on the S1R affinity and selectivity, we report (i) the differences in metabolism and pharmacokinetics, (ii) the in vivo behavior in different animal models, (iii) the in vitro autoradiography outcomes, and (iv) the dosimetric profiles. The successful use of the best-performing S1R PET radiotracers in the characterization of novel S1R drugs is also reported together with the approaches to assess the potential for clinical translation. What emerges from this review is that, although the development of reliable PET agents appears to be extremely challenging, these radiotracers hold incredible potential and play a fundamental role in the exploitation of S1R in health and disease. Full article
(This article belongs to the Section Medicinal Chemistry)
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20 pages, 1754 KB  
Article
Synthesis and Biological Evaluation of Novel Mixed-Ligand 99mTc-Labeled Anthraquinone Complexes as Potential DNA-Targeted Imaging Agents
by Theofanis Matthaios Migkos, Pigi Glykofridi, Georgios Paparidis, George Psomas, Ioannis S. Vizirianakis, Catherine Gabriel, Dimosthenis Sarigiannis, Ioannis Iakovou and Dionysia Papagiannopoulou
Inorganics 2025, 13(11), 368; https://doi.org/10.3390/inorganics13110368 - 3 Nov 2025
Viewed by 997
Abstract
Anthraquinones are molecules with numerous biological properties that can act as DNA intercalators and topoisomerase IIa inhibitors. In this work, the development of technetium-99m radiotracers was pursued via the technetium-tricarbonyl “2 + 1” mixed-ligand approach, fac-[99mTc][TcI(CO)3(NN′)(N)] [...] Read more.
Anthraquinones are molecules with numerous biological properties that can act as DNA intercalators and topoisomerase IIa inhibitors. In this work, the development of technetium-99m radiotracers was pursued via the technetium-tricarbonyl “2 + 1” mixed-ligand approach, fac-[99mTc][TcI(CO)3(NN′)(N)]+, with a (N,N′) bidentate chelator and a N co-ligand. In one approach, the ligands used were 2,2′-bipyridine (bpy) and N-functionalized-imidazole, where imidazole was conjugated to an anthraquinone moiety. In the other approach, 2-picolylamine and imidazole were used as the mixed-ligand system, where picolylamine was conjugated to an anthraquinone moiety. The synthesis of the ligands was achieved by reaction of 2-picolylamine with a suitably functionalized anthraquinone (Aqpa) or anthrapyrazole (Appa) and imidazole with a suitably functionalized anthraquinone (Aqim). The rhenium reference compounds, fac-[ReI(CO)3(bpy)(Aqim)]+ with bpy as a bidentate chelator and fac-[ReI(CO)3(Aqpa or Appa)(Im)]+, with imidazole (Im) as a co-ligand, were synthesized and characterized with spectroscopic methods. The radiotracer technetium-99m complexes fac-[99mTc][Tc(CO)3(bpy)(Aqim)]+ and fac-[99mTc][Tc(CO)3(Aqpa or Appa)(Im)]+ were prepared and characterized with standard methods. The purified radiotracers displayed high stability (≥90%) after incubation 24 h in 1 mM L-histidine or rat plasma. The tracers’ cell uptake was evaluated in vitro in CT-26 cells, and their pharmacokinetic properties and tumor uptake were evaluated in vivo in CT26-tumor-bearing mice. The “2 + 1” technetium-tricarbonyl approach leads to in vitro stable tracers, and this mixed-ligand system shows promise for further evaluation. Full article
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11 pages, 1190 KB  
Communication
Multi-Fused S,N-Heterocyclic Compounds for Targeting α-Synuclein Aggregates
by Chao Zheng, Jeffrey S. Stehouwer, Goverdhan Reddy Ummenthala, Yogeshkumar S. Munot and Neil Vasdev
Cells 2025, 14(19), 1531; https://doi.org/10.3390/cells14191531 - 30 Sep 2025
Cited by 1 | Viewed by 1271
Abstract
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 [...] Read more.
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 (Ki) 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
(This article belongs to the Special Issue Development of PET Radiotracers for Imaging Alpha-Synuclein)
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16 pages, 4477 KB  
Article
Forecasting 7Be Concentrations Using Time Series Analysis: A Case Study of Panama City
by Alexander Esquivel-López, Bernardo Fernández, Omayra Pérez, Felipe Castillo, Nathalia Tejedor-Flores and Mitzi Cubilla-Montilla
Atmosphere 2025, 16(9), 1104; https://doi.org/10.3390/atmos16091104 - 20 Sep 2025
Viewed by 1325
Abstract
Beryllium-7 (7Be) is widely used as an atmospheric radiotracer due to its short half-life and ease of detection. Its evaluation and forecasting provide valuable insights into atmospheric behavior and environmental processes. This study aimed to develop a robust explanatory and predictive [...] Read more.
Beryllium-7 (7Be) is widely used as an atmospheric radiotracer due to its short half-life and ease of detection. Its evaluation and forecasting provide valuable insights into atmospheric behavior and environmental processes. This study aimed to develop a robust explanatory and predictive model for 7Be concentrations in Panama using monthly data from 2006 to 2019 provided by the RN50 Station at the University of Panama. This study employed ARIMA models for time series analysis and forecasting, complemented by error metrics such as Root Mean Squared Error (RMSE), Mean Squared Error (MSE), Mean Absolute Error (MAE), and Mean Absolute Percentage Error (MAPE) to assess the accuracy of the results. After verifying data suitability, analyzing series components, and testing stationarity using the Dickey–Fuller test, the SARIMA (2,0,1) (2,1,0) model was identified as optimal. This model successfully forecasted 7Be concentrations for the final five months of 2019, offering a useful tool for understanding airborne particle dynamics in Panama and supporting future applications of 7Be in the study and estimation of soil erosion. Full article
(This article belongs to the Section Air Quality)
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