The global rise of theranostic nuclear medicine continues to increase the environmental and economic pressure associated with radiopharmaceutical production. Large-scale manufacturing, reliant on cyclotrons, GMP-compliant cleanrooms, automated synthesis modules, and disposable plastics, represent the most energy-intensive and waste-generating approach. In contrast, cold kit technologies represent an underutilized strategy to improve sustainability, reduce environmental impact and expand equitable global access to theranostic radiopharmaceuticals. This review evaluates small-scale hospital-based compounding using lyophilised cold kit technologies through the lens of green chemistry and environmental justice. Gallium-68 and lutetium-177 are used as representative theranostic radionuclides. Energy consumption, waste generation, and accessibility between large-scale and hospital-based production are considered, highlighting the reduced environmental footprint of cold kits. Attention is given to radionuclide waste streams, including long-lived contaminants such as germanium-68 and lutetium-177 m. Challenges associated with cold kit production, including radionuclide source variability, radiochemical robustness and occupational radiation protections are addressed. This review indicates that small-scale hospital compounding could contribute to a more sustainable, resource-efficient, and equitable nuclear medicine practice without compromising clinical quality or patient safety.
Integrin αvβ6 is minimally expressed in normal epithelial tissues but is upregulated in a wide range of malignancies and fibrotic diseases, where it is closely linked to epithelial remodeling, tumor invasion, and disease progression. Owing to its restricted expression pattern and biological significance, integrin αvβ6 has emerged as an attractive target for molecular imaging and targeted therapy. This review summarizes recent progress in the development of αvβ6-targeted radiopharmaceuticals, covering linear and cyclic peptide-based tracers as well as emerging theranostic agents. These advances have led to imaging agents with improved in vivo imaging performance and enhanced translational potential, while also highlighting the complementary biological information provided by imaging of integrin αvβ6 in oncology and fibrotic diseases. Several radiopharmaceuticals have entered early clinical evaluation, providing initial evidence for the clinical feasibility of αvβ6-specific imaging and supporting its further investigation in oncology and fibrosis. In parallel, the development of αvβ6-targeted radionuclide therapy has broadened the therapeutic landscape and strengthened interest in αvβ6-targeted theranostic strategies. Together, these developments support continued evaluation of αvβ6-targeted radiopharmaceuticals for precision imaging and theranostic applications.
The growing societal demand for novel radionuclides across medicine, industry, and science has intensified the need for sustainable and accessible radionuclide production pathways. In addition to dedicated production facilities, large accelerator complexes primarily designed for fundamental and applied nuclear science research offer a valuable complementary source of rare radionuclides. The Isotope Harvesting Program (IHP) at the Facility for Rare Isotope Beams (FRIB) at Michigan State University (MSU) represents a novel approach for the production and recovery of valuable radionuclides generated as by-products of routine high-power heavy-ion accelerator operations. By transforming otherwise discarded radioactive byproducts into scientifically useful radionuclides, isotope harvesting embodies a “wealth-from-waste” strategy aligned with the principles of green radiochemistry and sustainable resource utilization. Building on early proof-of-concept developmental work initiated at the National Superconducting Cyclotron Laboratory (NSCL) and subsequently expanded at FRIB, the isotope harvesting effort has demonstrated the recovery and purification of several scientifically important radionuclides. This approach enables access to non-conventional radionuclides for applications spanning nuclear medicine, fundamental nuclear physics, environmental science, astrophysics, national security, and industrial research.Integrated directly into the FRIB accelerator complex, the isotope harvesting infrastructure is designed to enable the collection of radionuclides generated during routine beam operations by recovering them from activated beam-dump cooling water, gaseous effluents, and irradiated components, without interfering with the facility's primary scientific mission. Although significant progress has been achieved, isotope harvesting remains an evolving field with ongoing challenges associated with radionuclide transport behavior, radiochemical separations, system integration, remote handling, and long-term operational reliability. This review summarizes the development and evolution of early-stage isotope harvesting activities at NSCL and FRIB, along with advances in facility infrastructure and emerging scientific and technical efforts, highlighting their roles in guiding future pathways for sustainable radionuclide production while advancing the goals of green radiochemistry.
BACKGROUND:Gastrin-releasing peptide receptor (GRPR) is overexpressed in several malignancies and is an attractive target for imaging and radioligand therapy. We recently reported [68Ga]Ga-DOTA-Pip-PEP-4 with favorable tumor uptake but also high pancreas uptake. In this study, we investigated whether replacing the piperidine moiety at AA14 in [68Ga]Ga-DOTA-Pip-PEP-4 with structurally distinct six-membered ring-containing derivatives could improve GRPR targeting and reduce pancreas uptake. METHODS:SP01010, SP01011, and SP01022 were synthesized by solid-phase synthesis and labeled with natGa/68Ga. GRPR binding affinities were determined by in vitro competition binding assays. Positron emission tomography (PET) imaging and biodistribution studies were performed in PC-3 tumor-bearing mice at 1 h post-injection. RESULTS:SP01010, SP01011, and SP01022 were synthesized in 39-51% yield, and their nonradioactive Ga-complexed standards were obtained in 69-82% yield. Ki(GRPR) values of Ga-SP01010, Ga-SP01011 and Ga-SP01022 were 4.29 ± 0.71, 2.79 ± 0.77, and 36.7 ± 5.11 nM, respectively. 68Ga-labeled tracers were obtained in 27-57% decay-corrected radiochemical yield with >95% radiochemical purity. All tracers enabled clear visualization of PC-3 tumor xenografts in PET images and the tumor uptake was highest for [68Ga]Ga-SP01011 (9.63 ± 1.07%ID/g), followed by [68Ga]Ga-SP01022 (4.17 ± 1.15%ID/g) and [68Ga]Ga-SP01010 (3.98 ± 0.40%ID/g). Their pancreas uptake ranged from 0.83 to 4.96%ID/g, significantly lower than that of [68Ga]Ga-DOTA-Pip-PEP-4 (24.8 ± 1.77%ID/g). CONCLUSION:Substitution of the piperidine moiety in [68Ga]Ga-DOTA-Pip-PEP-4 significantly influences GRPR binding and pharmacokinetics. [68Ga]Ga-SP01011 has enhanced tumor uptake and minimal pancreas uptake, highlighting its potential as a promising PET tracer for detecting GRPR-expressing cancer.
BACKGROUND:Recently, microsurgical restoration of extracranial lymphatic outflow through lymphatic-venous anastomosis (LVA) has been explored as a potential, albeit controversial, therapeutic strategy to enhance glymphatic clearance in Alzheimer's disease (AD); however, its impact on AD-related neuropathology has not yet been quantitatively or longitudinally evaluated. In this study, we performed translational PET imaging to determine whether restoring extracranial lymphatic outflow can rapidly and reversibly modulate cerebral glucose metabolism, myelin integrity, and amyloid burden in relation to cognitive improvement. METHODS:A cervical lymphatic obstruction model was established in rats, followed by longitudinal [18F]FDG-PET and [11C]MeDAS-PET to assess cerebral glucose metabolism and myelin integrity before and after LVA, with imaging findings further validated by immunohistochemistry. A cohort of eight AD patients underwent LVA and received [11C]PIB and [11C]MeDAS PET imaging at baseline and follow-up. The imaging results were correlated with cognitive performance. RESULTS:In Sprague-Dawley rats, cervical lymphatic obstruction led to significantly elevated cerebral glucose metabolism and reduced myelin integrity, both of which were largely restored to near-normal levels following LVA treatment, as further validated by immunohistochemical analyses. Similarly, in AD patients, LVA produced a 36.0 ± 2.1% decrease in cortical amyloid burden on [11C]PIB-PET (p < 0.001) and a 59.8 ± 29.0% increase in [11C]MeDAS uptake (p = 0.005). Subsequent correlation with MMSE scores demonstrated that short-term cognitive improvement was associated with greater myelin restoration and greater amyloid reduction. CONCLUSION:These preliminary findings provide initial evidence that restoration of extracranial lymphatic outflow may modulate core neuropathological processes in AD, justifying further investigation in larger cohorts with appropriate control groups and randomized controlled designs to validate and extend these observations. TRIAL REGISTRATION:The study was registered on the Chinese Clinical Trial website on April 21, 2025 (Registration No. ChiCTR2500101149).
INTRODUCTION:In targeted radionuclide therapy, high renal radioactivity raises concerns that nephrotoxicity may limit therapeutic utility. Our recently developed 211At-labeled tetravalent RGD peptide ([211At]At-(RGD)4) also faces this challenge, despite achieving high and persistent tumor accumulation. Here, we evaluated whether introducing renal brush-border enzyme-cleavable linkers (renal brush-border strategy) could reduce renal radioactivity and improve the tumor-to-kidney ratio of radiolabeled tetravalent RGD peptides. 125I-labeled analogues were used due to limited availability of 211At. METHODS:Gly-Lys (GK) or Gly-Asp (GD) linkers were inserted between the radiolabeling moiety and the tetravalent RGD peptide. The biodistribution of [125I]GK-(RGD)4 and [125I]GD-(RGD)4 was evaluated in nude mice bearing U87MG human glioblastoma. Metabolite analysis was performed using urine, kidney, and tumor samples. U87MG cells were incubated with [125I]I-(RGD)4 or [125I]GD-(RGD)4 in the presence or absence of lysosomal enzyme inhibitors. Fluorescently labeled tetravalent RGD peptide (FL-(RGD)4) was used to evaluate cellular internalization. RESULTS:Both [125I]GK-(RGD)4 and [125I]GD-(RGD)4 showed reduced renal retention compared with [125I]I-(RGD)4 but also exhibited decreased tumor retention, resulting in an unchanged tumor-to-kidney ratio. [125I]iodohippuric acid was detected in the tumor, kidney, and urine samples, confirming in vivo linker cleavage. Lysosomal enzyme inhibition restored the cellular accumulation of [125I]GD-(RGD)4 to levels comparable to [125I]I-(RGD)4. Fluorescence microscopy visualized internalization of FL-(RGD)4 followed by trafficking to lysosomal compartments. CONCLUSION:GK and GD linkers reduced renal radioactivity but impaired tumor retention, likely due to internalization and lysosomal linker cleavage. These findings clarify both the utility and limitations of the renal brush-border strategy for improving tumor-to-kidney ratios.
AIM:Our goal was to establish a preclinical model that simulates prostate cancer (PCa)-derived, but PSMA-negative (PSMA-) bone metastasis, which can be visualized via single-photon emission computed tomography (SPECT) and to compare 111In- and 99mTc-labeled bone-seeking agents, ideally by using this animal model. METHODS:Intraosseous (i.o.) inoculations of PC-3 cells (5 × 105) were conducted in 10-to-11-week-old male CB-17 SCID mice (n = 6). Over a period of three weeks, 19.6-81.1 MBq (0.03-0.12 mg, n = 18) [99mTc]Tc-DPD was injected once per week into treated mice and bone lesion formation was investigated by μSPECT/CT (2 h/4 h and 22-23 h post injectionem (p.i.)). 48.9-78.7 MBq (0.03-0.04 mg or 44.8-72.7 nmol, n = 6) [111In]In-BPAMD was injected in healthy, non-treated 10-to-14-week-old male CB-17 SCID mice (n = 4) and skeletal uptake investigated by μSPECT/CT (2 h and 22-24 h p.i.). RESULTS:In comparison to the untreated tibia or femur, no increased uptake of [99mTc]Tc-DPD could be visualized by μSPECT/CT in the i.o. inoculated tibia or femur. [99mTc]Tc-DPD showed considerable uptake throughout the entire skeleton of the mice (9.02% ID/mL in the spine) and surpassed bone uptake of [111In]In-BPAMD (0.28% ID/mL) by a factor of 32 at 2 h p.i. Biodistribution studies at 23-24 h p.i. confirmed these results. CONCLUSION:[111In]In-BPAMD could not compete with [99mTc]Tc-DPD in μSPECT/CT imaging of bone structures in CB-17 SCID mice. In this proof-of-concept study, a preclinical model for PCa-derived bone metastasis, which exhibits enhanced uptake of [99mTc]Tc-DPD could not be established by intraosseous inoculation of PC-3 cells in CB-17 SCID mice.
BACKGROUND:Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer subtype, representing 70-80% of cases. Its unique molecular profile and therapeutic resistance make it a key focus in oncology. Recent advances in targeting the ccRCC-specific biomarker carbonic anhydrase IX (CAIX), especially through radiolabeled small-molecule inhibitors, are revolutionizing its management. METHODS:We conducted a systematic literature search using PubMed, Web of Science, ACS, and CAS databases to identify promising small-molecule CAIX-targeted radiopharmaceuticals for ccRCC published between 2011 and early 2026. RESULTS:This review systematically outlines the biology and pathological role of CAIX in ccRCC, and surveys the landscape of CAIX-targeted radioligands under investigation-from acetazolamide and benzenesulfonamide to cyclic peptide-based probes. It also presents single-photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging results for selected promising candidates. We critically assess the current state and promise of theranostics, highlighting future directions and challenges. By summarizing key clinical findings, this work aims to inform the development of CAIX-targeted radiopharmaceuticals and to promote precision medicine in ccRCC. CONCLUSIONS:[68Ga]Ga-NY104, [99mTc]Tc-PHC-102, [68Ga]Ga-DPI-4452, [18F]F-VM4-037 and [18F]F-U-104 exhibit promising CAIX targeting. Structural optimization of these compounds holds promise for developing CAIX inhibitors with enhanced selectivity and lower toxicity for ccRCC therapy. At the clinical translation level, a series of novel probes represented by [68Ga]Ga-NY104 and [64Cu]Cu-PD-32766 have entered clinical investigation, enabling high-sensitivity and high-specificity detection of both primary and metastatic ccRCC lesions via PET/CT imaging. Moreover, theranostic platforms based on identical molecular scaffolds (e.g., US2 platform, DPI-4452) have laid the foundation for a "see-and-treat" precision medicine paradigm.
Fibroblast activation protein (FAP) is highly expressed in cancer-associated fibroblasts across most epithelial tumors but FAP is nearly absent in normal tissues, making it an attractive target for cancer imaging and therapy. Small-molecule FAP inhibitors have emerged as potent imaging tracers due to their rapid tumor uptake and high tumor-to-background ratios (TBRs), although their short tumor residence limits therapeutic applications. To improve pharmacokinetics and expand theranostic potential, we developed a novel library of FAP inhibitors (eFAPs) based on an 8-quinoline-cyanopyrrolidine scaffold. Structural modifications were introduced by varying linker length between the pharmacophore and chelator, altering global charge, and modulating hydrophilicity. All eFAPs were highly hydrophilic (LogD7.4: -3.2 to -3.7) and demonstrated strong inhibition of both human and murine FAP (IC50, human FAP < 3 nM and IC50, murine FAP < 4 nM, respectively), with high selectivity against prolyl oligopeptidase (PREP) and dipeptidyl peptidase-4 (DPP4). Radiolabeling with [111In]In achieved >96% radiochemical yield for the majority of the derivatives, with overall good stability in PBS and serums up to 24 h. In HT-1080.hFAP cells, eFAPs showed specific uptake (10.2 ± 1.9%-25.8 ± 4.5% AD), with eFAP-9 exhibiting the highest uptake, superior to the clinical reference FAPI-46 (17.5 ± 4.4% AD). In vivo SPECT/CT imaging revealed rapid blood clearance and tumor accumulation, resulting in clear tumor visualization sustained for up to 48 h for eFAP-12. Biodistribution confirmed strong tumor uptake of eFAP-9 (7.95 ± 3.68%ID/g), comparable to FAPI-46 (8.55 ± 1.28%ID/g) at 1 h p.i., and prolonged tumor half-life of eFAP-12 (6.01 h), which was 1.7-fold longer than FAPI-46 (2.84 h).
BACKGROUND:YntraDose™ is a novel injectable radiotherapeutic formulation combining BioGlue® (bovine serum albumin-glutaraldehyde polymer) with Yttrium-90 resin microspheres. This pilot preclinical feasibility study represents the first in vivo evaluation of YntraDose™ administration into lung tissue and was designed to assess its injectability, polymerization performance, biodistribution, dosimetry, and tissue response. METHODS:Seven healthy female Landrace pigs were enrolled and received ultrasound-guided percutaneous injections of YntraDose™ in two lung lobes (5 ml and 10 ml syringes targeting 150-185 MBq). Pigs were euthanized at 24 h, 7-, 14-, and 21 days post-injection for necropsy, PET/CT imaging, dosimetry, and histological evaluation. Immunohistochemistry for IL-1β, IL-6, and IL-8 was performed on lung biopsies to assess inflammatory activity. RESULTS:YntraDose™ administration was feasible and resulted in localized polymerization within the injection site, with no evidence of radioactivity spread to other organs. Histological analysis revealed areas of necrosis extending up to 1-1.5 cm from the main deposition site and diffuse inflammatory cell infiltration. IL-1β, IL-6, and IL-8-positive cells were identified throughout the tissue, indicating a strong inflammatory response. CONCLUSIONS:This first in vivo preclinical investigation demonstrates that YntraDose™ can be successfully injected and polymerized in lung tissue, even at high radioactivity levels. Despite the intense inflammatory reaction observed, the results support further preclinical studies with optimized, clinically relevant 90Y activities to evaluate the potential of YntraDose™ for localized lung tumor ablation.
BACKGROUND:Fibroblast Activation Protein (FAP) is a critical target for imaging cancer-associated fibroblasts and active hepatic stellate cells in liver fibrosis. While FAPI-2286 has been widely explored with 68Ga and 177Lu, the use of copper-64 offers unique advantages for theranostics due to its amenable half-life and chemical pairing with therapeutic copper-67. This study focuses on the automated radiosynthesis of [64Cu]Cu-FAPI-2286 in a green synthetic route, detailed physicochemical characterization, quality control analysis, and initial clinical evaluation of [64Cu]Cu-FAPI-2286 in liver fibrosis. METHODS:The [64Cu]Cu-FAPI-2286 was synthesized via manual and automated modules using aqueous solution of [64Cu]CuCl2. The reaction conditions (solvent, temperature, time) were optimized. Physicochemical evaluation included lipophilicity (logD7.4) and stability challenges against EDTA, physiological media, and human serum. A pilot PET/CT scan was performed on a patient with HCV-related decompensated cirrhosis complicated by Grade III ascites to assess biodistribution and hepatic uptake. RESULTS:Optimized automated synthesis in aqueous medium at 40 °C yielded [64Cu]Cu-FAPI-2286 with >95% radiochemical purity and an apparent molar activity (AMA) of 258 ± 5 MBq/μmol. The radiotracer demonstrated high hydrophilicity with a logD7.4 value of -2.38 ± 0.01. The complex exhibited excellent stability (>95%) in serum and saline over 24 h and showed strong resistance to transchelation against a 500-fold excess of EDTA. Clinically, the patient with liver fibrosis demonstrated intense, diffuse hepatic uptake with a SUVmax(lbm) of 17.54, significantly higher than background, confirming active fibrogenesis. CONCLUSION:We successfully established a robust, green, automated synthesis route for [64Cu]Cu-FAPI-2286. The tracer's favorable hydrophilicity and stability make it a promising agent. The high uptake observed in the fibrotic liver highlights its potential as a non-invasive biomarker for staging liver fibrosis and for guiding future [67Cu]Cu-FAPI-2286 therapies.
Introduction Sustainable green radiochemistry is the result of current research, in which radiolabeling strategies are increasingly being developed in the direction of kit labeling. This includes the use of sunlight for reactions, but also tailor-made chelators allowing a to quantitative chelation of the corresponding radionuclide even at temperatures around 20 °C. The ultimate goal is to use these reaction conditions for labeling kit development in which only the radionuclide needs to be added and the reaction then occurs quantitatively in a sterile vial. Chelators such as HBED are already included in approved kits for the production of [68Ga]Ga-PSMA-11 (Locametz®, IsoPROtrace11®, and Illuccix®) and allow radiolabeling at 20 °C. This paper reports on the semi-automatic labeling method of macropa(mcp)-based PSMA derivatives with 225Ac, which was performed at 20 °C without heating and, according to subsequent quality control, is technically ready-to-use for patient applications. To further strengthen the green aspect, critical chemicals like environmental persistent trifluoroacetic acid (TFA) were considered to be replace against more eco-friendly chemicals. Furthermore, additives like ascorbic acid or DTPA, which are usually used for protection against radiolysis or scavenge free progenies were considered to be eliminated from the process due to the reason, that the mcp-based precursor might be able to rechelate free progenies, as soon as they are generated from their parent nuclide 225Ac. Methods An iQS module was equipped with sterile single-use components and an already automated radiolabeling process was adopted to the semi-automatic system. Three validation batches for two different mcp-based PSMA derivatives were produced including quality control with criteria fulfilling clinical standards. Results Three consecutive validation batches were successfully produced for each mcp-M-PSMA and mcp-D-PSMA derivatives to evaluate the safety and robustness of the labeling method. Overall, the six batches reached radiochemical yields >80% and hit the quality parameters such as radiochemical purity of >95% for clinical application.Additionally, the replacement of environmental persistent TFA of the HPLC eluents with phosphoric acid (H3PO4) led to similar retention times combined with a higher resolution in the radio-HPLC chromatograms.The effect of rechelation was carefully evaluated using an excess amount of precursor. It was found that, with increasing concentration, a rechelation of free progenies occurred from 22 to 144 h. Either the reaction solution or the diluted product solution was analyzed by TLC and HPLC. Conclusions The electroless synthesis of 225Ac-mcp-PSMA derivatives was successfully implemented to the iQS module, and the products fulfilled all criteria for patient application. H3PO4 has successfully replaced environmental persistent TFA within the HPLC eluents. With the use of mcp-based precursors, the addition of radiolysis protection agents was no longer mandatory. Rechelation of free progenies was observed at higher precursor concentration from 22 up to 144 h in the diluted product solutions. In future, this labeling method could be used for safe production of 225Ac-labeled macropa-containing peptides without electricity. Advances in knowledge Mcp-based precursors enable for electroless reactions at 20 °C yielding 225Ac-radiopharmaceuticals with 10× increased molar activity compared to DOTA- or DOTAGA-based precursors and diluted product solution leads to higher stability and lesser radiolysis due to the rechelation effect compared to the reaction solutions.
Background Gallium-68 (68Ga) is a PET isotope that is finding more use in the clinical setting as a PET diagnostic tool, for example 68Ga PSMA is widely used in the diagnosis of prostate cancer, and 68Ga dotatate for the diagnosis of neuroendocrine tumors. Current production is mostly performed using either 68Ge/68Ga generators or liquid targets containing 68Zn and irradiated with protons in an accelerator. Recently, GE Healthcare published an article describing the irradiation and purification of 68Ga using a solid 68Zn target. This article describes an electroplating process used to produce 68Zn targets. Method The method to produce 68Zn cyclotron targets for 68Ga production by electroplating zinc-68 onto a 1” diameter 99.99% natural silver planchette is described. Each target had differing plated masses, ranging from 40 to 170 mg using an electroplating solution produced from purified zinc-68 effluent from prior, non-solid target based 68Ga production processes. The targets were irradiated using a GE PET cyclotron proton beam with an energy of 16.5 MeV and beam current approximately 80 mA. Radiochemical yields of purified gallium-68 resulting from the dissolution of each target were measured using preliminary HPGe results to determine gallium-68 yield. The gallium-68-specific gamma emission at 1077.3 keV, as opposed to the indirect emission at 511 keV, was used to determine the amount of 68Ga present in the sample. In addition, the amount of stable metal contaminants (Zn, Fe, Ag and Al) were measured using qualitative ICP-OES. Results The targets produced using this technique were stable to both mild-mechanical abrasion (wipe with non-metallic material and washing with water) and irradiation by a 16.5 MeV cyclotron proton beam. Based on initial data, the optimum plating mass for 68Zn targets is between 60 mg and 160 mg. This applies to targets produced by this method and subsequently irradiated, digested, and purified using GE Healthcare equipment and protocols. Conclusion This article provides methodology to produce 68Zn solid targets for cyclotron production of 68Ga. The initial results from 68Ga specific quality control analytical techniques demonstrate the potential for establishing a GMP-compliant production process within an academic or hospital setting.
BACKGROUND:The introduction of radiolabeled nanoparticles in the realm of brachytherapy has led to a promising therapeutic strategy for cancer management called 'nanobrachytherapy'. In the quest of developing a potent radiolabeled inorganic biomaterial for use in nanobrachytherapy, we report the synthesis and evaluation of 169Yb [T1/2 = 32.02 d]-labeled glucuronic acid (GA) functionalised hydroxyapatite (HA) nanoparticles (GAHAnp) and established its potency in pre-clinical settings. METHODS:GAHAnp having average hydrodynamic diameter of 45 ± 3 nm was synthesized and characterized using various analytical methods. Ytterbium-169 was produced with adequate radionuclidic purity by direct neutron activation of isotopically enriched Yb-target in research reactor. Radiolabeling protocol of GAHAnp with 169Yb to obtain [169Yb]Yb-GAHAnp in high yield and purity was optimized. Adsorption of [169Yb]Yb3+ on GAHAnp followed Langmuir-Freundlich isotherm and pseudo-second order kinetics. The mechanism of incorporation of [169Yb]Yb+3 on GAHAnp was investigated using density functional theory (DFT) and experimentally verified by radiotracer investigations and XAFS studies, which suggested replacement of Ca2+ with Yb3+ in GAHAnp matrix. The [169Yb]Yb-GAHAnp formulation demonstrated excellent in vitro radiochemical stability in physiological media and cell toxicity in Raji cells. SPECT/CT imaging and ex vivo biodistribution carried out after intra-tumoral administration of [169Yb]Yb-GAHAnp in tumor bearing mice showed near-complete retention of the formulation in the tumor mass upto 2 weeks. Tumor growth could be significantly arrested after administration of 30 MBq dose of the formulation compared to the control. CONCLUSIONS:These findings demonstrate the potential utility of synthesized [169Yb]Yb-GAHAnp formulation in the treatment of solid tumors through nanobrachytherapy.
Background Fibroblast activation protein alpha (FAP) is a pan-tumor target highly expressed on cancer-associated fibroblasts. We developed 4AH29, a single-domain antibody binding FAP, and investigated the biodistribution of [131I]I-GMIB-4AH29 and [111In]In-DOTA-4AH29 in Göttingen minipigs. Methods Following radiopharmaceutical administration, blood activity profile was determined by gamma-counter and biodistribution kinetics were determined using SPECT/CT imaging, respectively. The data obtained with [111In]In-DOTA-4AH29 were used as a surrogate for its 177Lu- and 225Ac-labeled analogues and extrapolation to human absorbed dose was calculated for all analogues. Results Radiolabeled 4AH29 showed good tolerability within the studied time frame. It displayed fast blood clearance driven by renal excretion. Kidney clearance dynamics of [131I]I-GMIB-4AH29 and [111In]In-DOTA-4AH29 were distinct, likely driven by the different radiolabeling chemistry for halogen or metal conjugation. However, the contrasting patterns did not translate into relevant differences in mean residence time (MRT), nor was there a significant difference in bone marrow or liver MRTs when comparing halogen and metal-radiolabeled 4AH29. Extrapolated human absorbed doses for [131I]I-GMIB-4AH29 and [177Lu]Lu-DOTA-4AH29 were compared given their similar particle decay and comparable physical half-lives. In kidneys, [131I]I-GMIB-4AH29 led to an extrapolated human absorbed dose of 8.23E-01 mGy/MBq, whereas [177Lu]Lu-DOTA-4AH29 reached 5.86E-01 mGy/MBq. Consequently, the maximum tolerable administered activities were 28 and 39 GBq, respectively, to reach the renal absorbed dose limit of 23 Gy as determined by external beam radiation therapy (EBRT). In red marrow, the equivalent dose for [131I]I-GMIB-4AH29 was 3.8E-02 mGy/MBq and 1.36E-02 mGy/MBq with [177Lu]Lu-DOTA-4AH29. Thus, 53 GBq and 148 GBq can be administered, respectively, before reaching the EBRT set absorbed dose threshold of 2 Gy. Conclusion 4AH29 radiolabeled with 131I or 111In is well tolerated in Göttingen minipigs within the studied time frame. Extrapolated dosimetry of radiolabeled 4AH29 using OLINDA software indicates that its administration within a clinically relevant range is possible without exceeding toxicity limits in critical organs.
Pretargeted positron emission tomography (PET) is emerging as a transformative approach for imaging biologics in the brain, overcoming the limitations of direct radiolabeling. Conventional methods with long-lived radionuclides suffer from high radiation exposure, off-target accumulation, and suboptimal imaging properties. Pretargeting separates the targeting from the imaging step, enabling the use of short-lived radionuclides such as fluorine-18, the clinical gold standard, and thereby allowing high-contrast, low-dose imaging. Realizing this strategy in the brain remains challenging due to the restrictive blood-brain barrier, pharmacokinetic constraints, and the requirement for efficient in vivo click chemistry. Recent progress spanning in silico design, in vitro validation, and in vivo studies has now demonstrated successful pretargeting with BBB-shuttled antibodies and antisense oligonucleotides in rodents, non-human primates, and Alzheimer's disease models. Together, these studies demonstrate that what was once considered utopian has now become reality.
Neuroendocrine tumors (NETs) represent a clinically heterogeneous group of malignancies originating from neuroendocrine cells, with the potential to arise in nearly any organ system. Despite their relatively low incidence, NETS are associated with significant morbidity and mortality, with reported 1- and 5-year mortality rate of 27.2% and 60.4%, respectively. These statistics underscore the critical importance of early and accurate diagnosis. A hallmark of NET biology is the overexpression of somatostatin receptors (SSTRs) on NET cell membranes. This molecular feature has been effectively exploited for both imaging and through the use of radiolabeled somatostatin analogues. To date, three FDA-approved radiopharmaceuticals for PET imaging of somatostatin receptor positive (SSTR+) NETs are clinically available, establishing PET as the standard imaging modality for disease detection, staging, and treatment planning of NETs. However, current tracers are limited by either the short half-lives or by practical constraints in production and distribution, restricting their broader clinical utility. 89Zr (t1/2 = 3.27 days, β+ = 22.3%, β+avg = 395.5 keV) offers an attractive alternative, enabling imaging at extended timepoints with improved tumor-to-background contrast and the potential for more accurate pretherapy dosimetry. The aim of this work is to evaluate [89Zr]Zr-DFO-TATE and [89Zr]Zr-DFO-TOC for PET imaging of SSTR+ NETs. This study seeks to provide a comprehensive in vivo comparison of the two agents including the in vivo PET imaging, ex vivo biodistribution, and internal radiation dosimetry, with the overarching goal of advancing precision diagnostics and improving therapeutic planning for NET patients undergoing [177Lu]Lu-DOTA-TATE therapy.
Lung cancer is a leading cause of cancer-related mortality worldwide, with high metastatic potential and limited imaging tools for guiding targeted therapies. Poly(ADP-ribose) polymerase (PARP)-1 is overexpressed in multiple malignancies and represents a promising target for molecular imaging. Here, we evaluated the feasibility and specificity of [18F]Fluorthanatrace ([18F]FTT), a radiolabeled PARP inhibitor analogue, for noninvasive detection of lung cancer metastases in a syngeneic mouse model. Lung metastases were established by intravenous injection of LL/2 cells into C57BL/6 mice, followed by micro-CT and dynamic/static PET imaging. [18F]FTT showed high radiochemical purity (>99%) and remained stable in vitro. Dynamic PET identified 30-45 min postinjection as the optimal imaging window (tumour-to-lung ratio: 2.15 ± 0.10). Tumour uptake was significantly reduced by pre-administration of olaparib, confirming PARP-1-specific binding. Ex vivo autoradiography and immunohistochemistry demonstrated colocalization of tracer uptake with PARP-1 expression. Together, these results support the translational potential of [18F]FTT PET imaging for detecting PARP-1-expressing lung metastases in precision oncology.
