Charting the coordinative landscape of the 18F-Sc/44Sc/177Lu triad with the tri-aza-cyclononane (tacn) scaffold.

The widely established PET isotope 18F does not have a therapeutic partner. We have recently established that the Sc-F bond can be formed under aqueous, high yielding conditions, paving the way to providing 18F as diagnostic partners to 47Sc and 177Lu radiotherapeutics. Here, we synthesized a library of tacn-based chelators comprised of 10 structurally unique permutations incorporating acetate, methyl-benzylamide and picolinate donor arms. The chelator library encompasses chelators ranging from 6- to 9-dentate, and produces complex changes ranging from +3 to -1. The corresponding Sc-F/Sc and Lu chelate complexes were characterized using computational, spectroscopic and potentiometric methods, followed by optimization of radiolabeling with 18F, 44Sc and 177Lu and concluded by in vivo validation. We identify characterization benchmarks that chart the coordinative landscape of radiochelation approaches for this unusual triad. Our screening identifies two ligand systems, H2L111 and H3L201 as ideal, readily functionalizable constructs for prospective, targeted theranostic applications with 18F/44Sc/177Lu.

Radiochemistry and Complex Formation of the Cyclen-Derived Chelator DOTI-Me with Mn2+, Cu2+, Zn2+, Ga3+, In3+, Tb3+, and Lu3.

In this work, we describe the complex formation and radiochemistry of the cyclen-based chelator DOTI-Me bearing four methylimidazole arms. Radiolabeling properties were evaluated for 52gMn, 64Cu, 68Ga, 111In, 161Tb, and 177Lu, and DOTI-Me showed distinct differences to the structurally related H4DOTA. While radiochemical conversions (RCCs) for 52gMn and 111In were comparable to those of H4DOTA, DOTI-Me was not suited for 68Ga. Conversely, quantitative RCCs were achieved for 64Cu at ambient temperature, while elevated temperatures were required for complexation with H4DOTA. For 161Tb and 177Lu, good but not quantitative RCCs were obtained with DOTI-Me. With the exemption of 68Ga3+, radiolabeled complexes showed high stability in ligand challenge experiments and in human serum. X-ray analysis of the nonradioactive complexes revealed the formation of 8-coordinate Mn2+ and In3+ DOTI-Me complexes. Cu2+ adopted a unique distorted square-pyramidal 2 + 3 with the neutral DOTI-Me ligand and a Jahn-Teller distorted 4 + 2 coordination geometry for the diprotonated H2DOTI-Me2+ cation, respectively. For Zn2+, the complex with HDOTI-Me+ showed a distorted 4 + 3 pentagonal bipyramidal geometry. Summarizing, the ligand DOTI-Me may be an interesting alternative to H4DOTA for 52gMn, 64Cu, 111In, 161Tb, and 177Lu, covering diagnostic as well as therapeutic radionuclides. Further studies of targeted radiopharmaceuticals based on the DOTI-Me scaffold in combination with the set of radiometals presented herein are thus warranted.

Controlling the Redox Chemistry of Cobalt Radiopharmaceuticals.

The elementally matched 55Co (t1/2 = 17.53 h, Iß+ = 77%)/58mCo (t1/2 = 9.10 h, IC= 100%) radioisotope pair is of interest for development of paired diagnostic/therapeutic radiopharmaceuticals. Due to the accessibility of the Co2+/3+ redox couple, the redox state can be readily modulated. Here, we show that macroscopic and radiochemical redox reactions can be closely monitored and controlled using spectroscopic and radiochemical methods. We employ model systems to inform how to selectively synthesize thermodynamically favored coordination complexes. In addition to exogenous oxidants, our data indicates that 55Co-induced radiolysis of water efficiently and directly drives selective oxidation to the Co3+ species under no-carrier added (n.c.a.) conditions. Our synthetic strategies subsequently stabilize the respective 55Co2+ or 55Co3+ species for targeted Co-compounds' imaging in a mouse tumor model.

Investigating the In Vivo Biodistribution of Extracellular Vesicles Isolated from Various Human Cell Sources Using Positron Emission Tomography.

Positron emission tomography (PET) is a powerful tool for investigating the in vivo behavior of drug delivery systems. We aimed to assess the biodistribution of extracellular vesicles (EVs), nanosized vesicles secreted by cells isolated from various human cell sources using PET. EVs were isolated from mesenchymal stromal cells (MSCs) (MSC EVs), human macrophages (Mϕ EVs), and a melanoma cell line (A375 EVs) by centrifugation and were conjugated with deferoxamine for radiolabeling with Zr-89. PET using conjugated and radiolabeled EVs evaluated their in vivo biodistribution and tissue tropisms. Our study also investigated differences in mouse models, utilizing immunocompetent and immunocompromised mice and an A375 xenograft tumor model. Lastly, we investigated the impact of different labeling techniques on the observed EV biodistribution, including covalent surface modification and membrane incorporation. PET showed that all tested EVs exhibited extended in vivo circulation and generally low uptake in the liver, spleen, and lungs. However, Mϕ EVs showed high liver uptake, potentially attributable to the intrinsic tissue tropism of these EVs from the surface protein composition. MSC EV biodistribution differed between immunocompetent and immunodeficient mice, with increased spleen uptake observed in the latter. PET using A375 xenografts demonstrated efficient tumor uptake of EVs, but no preferential tissue-specific tropism of A375 EVs was found. Biodistribution differences between labeling techniques showed that surface-conjugated EVs had preferential blood circulation and low liver, spleen, and lung uptake compared to membrane integration. This study demonstrates the potential of EVs as effective drug carriers for various diseases, highlights the importance of selecting appropriate cell sources for EV-based drug delivery, and suggests that EV tropism can be harnessed to optimize therapeutic efficacy. Our findings indicate that the cellular source of EVs, labeling technique, and animal model can influence the observed biodistribution.

Effects of clinically relevant radionuclides on the activation of a type I interferon response by radiopharmaceuticals in syngeneic murine tumor models.

Radiopharmaceutical therapies (RPT) activate a type I interferon (IFN1) response in tumor cells. We hypothesized that the timing and amplitude of this response varies by isotope. We compared equal doses delivered by 90 Y, 177 Lu, and 225 Ac in vitro as unbound radionuclides and in vivo when chelated to NM600, a tumor-selective alkylphosphocholine. Response in murine MOC2 head and neck carcinoma and B78 melanoma was evaluated by qPCR and flow cytometry. Therapeutic response to 225 Ac-NM600+anti-CTLA4+anti-PD-L1 immune checkpoint inhibition (ICI) was evaluated in wild-type and stimulator of interferon genes knockout (STING KO) B78. The timing and magnitude of IFN1 response correlated with radionuclide half-life and linear energy transfer. CD8 + /Treg ratios increased in tumors 7 days after 90 Y- and 177 Lu-NM600 and day 21 after 225 Ac-NM600. 225 Ac-NM600+ICI improved survival in mice with WT but not with STING KO tumors, relative to monotherapies. Immunomodulatory effects of RPT vary with radioisotope and promote STING-dependent enhanced response to ICIs in murine models. Teaser: This study describes the time course and nature of tumor immunomodulation by radiopharmaceuticals with differing physical properties.

Synthesis of 64Cu-, 55Co-, and 68Ga-Labeled Radiopharmaceuticals Targeting Neurotensin Receptor-1 for Theranostics: Adjusting In Vivo Distribution Using Multiamine Macrocycles.

The development of theranostic radiotracers relies on their binding to specific molecular markers of a particular disease and the use of corresponding radiopharmaceutical pairs thereafter. This study reports the use of multiamine macrocyclic moieties (MAs), as linkers or chelators, in tracers targeting the neurotensin receptor-1 (NTSR-1). The goal is to achieve elevated tumor uptake, minimal background interference, and prolonged tumor retention in NTSR-1-positive tumors. Methods: We synthesized a series of neurotensin antagonists bearing MA linkers and metal chelators. The MA unit is hypothesized to establish a strong interaction with the cell membrane, and the addition of a second chelator may enhance water solubility, consequently reducing liver uptake. Small-animal PET/CT imaging of [64Cu]Cu-DOTA-SR-3MA, [64Cu]Cu-NT-CB-NOTA, [68Ga]Ga-NT-CB-NOTA, [64Cu]Cu-NT-CB-DOTA, and [64Cu]Cu-NT-Sarcage was acquired at 1, 4, 24, and 48 h after injection using H1299 tumor models. [55Co]Co-NT-CB-NOTA was also tested in HT29 (high NTSR-1 expression) and Caco2 (low NTSR-1 expression) colorectal adenocarcinoma tumor models. Saturation binding assay and internalization of [55Co]Co-NT-CB-NOTA were used to test tracer specificity and internalization in HT29 cells. Results: In vivo PET imaging with [64Cu]Cu-NT-CB-NOTA, [68Ga]Ga-NT-CB-NOTA, and [55Co]Co-NT-CB-NOTA revealed high tumor uptake, high tumor-to-background contrast, and sustained tumor retention (≤48 h after injection) in NTSR-1-positive tumors. Tumor uptake of [64Cu]Cu-NT-CB-NOTA remained at 76.9% at 48 h after injection compared with uptake 1 h after injection in H1299 tumor models, and [55Co]Co-NT-CB-NOTA was retained at 60.2% at 24 h compared with uptake 1 h after injection in HT29 tumor models. [64Cu]Cu-NT-Sarcage also showed high tumor uptake with low background and high tumor retention 48 h after injection Conclusion: Tumor uptake and pharmacokinetic properties of NTSR-1-targeting radiopharmaceuticals were greatly improved when attached with different nitrogen-containing macrocyclic moieties. The study results suggest that NT-CB-NOTA labeled with either 64Cu/67Cu, 55Co/58mCo, or 68Ga (effect of 177Lu in tumor to be determined in future studies) and NT-Sarcage labeled with 64Cu/67Cu or 55Co/58mCo may be excellent diagnostic and therapeutic radiopharmaceuticals targeting NTSR-1-positive cancers. Also, the introduction of MA units to other ligands is warranted in future studies to test the generality of this approach.

Targeting both GD2 and B7-H3 using bispecific antibody improves tumor selectivity for GD2-positive tumors.

Objectives: Disialoganglioside 2 (GD2), overexpressed by cancers such as melanoma and neuroblastoma, is a tumor antigen for targeted therapy. The delivery of conventional IgG antibody technologies targeting GD2 is limited clinically by its co-expression on nerves that contributes to toxicity presenting as severe neuropathic pain. To improve the tumor selectivity of current GD2-targeting approaches, a next-generation bispecific antibody targeting GD2 and B7-H3 (CD276) was generated. Methods: Differential expression of human B7-H3 (hB7-H3) was transduced into GD2+ B78 murine melanoma cells and confirmed by flow cytometry. We assessed the avidity and selectivity of our GD2-B7-H3 targeting bispecific antibodies (INV34-6, INV33-2, and INV36-6) towards GD2+/hB7-H3- B78 cells relative to GD2+/hB7-H3+ B78 cells using flow cytometry and competition binding assays, comparing results an anti-GD2 antibody (dinutuximab, DINU). The bispecific antibodies, DINU, and a non-targeted bispecific control (bsAb CTRL) were conjugated with deferoxamine for radiolabeling with Zr-89 (t1/2 = 78.4 h). Using positron emission tomography (PET) studies, we evaluated the in vivo avidity and selectivity of the GD2-B7-H3 targeting bispecific compared to bsAb CTRL and DINU using GD2+/hB7-H3+ and GD2+/hB7-H3- B78 tumor models. Results: Flow cytometry and competition binding assays showed that INV34-6 bound with high avidity to GD2+/hB7-H3+ B78 cells with high avidity but not GD2+/hB7-H3+ B78 cells. In comparison, no selectivity between cell types was observed for DINU. PET in mice bearing the GD2+/hB7-H3- and GD2+/hB7-H3+ B78 murine tumor showed similar biodistribution in normal tissues for [89Zr]Zr-Df-INV34-6, [89Zr]Zr-Df-bsAb CTRL, and [89Zr]Zr-Df-DINU. Importantly, [89Zr]Zr-Df-INV34-6 tumor uptake was selective to GD2+/hB7-H3+ B78 over GD2+/hB7-H3- B78 tumors, and substantially higher to GD2+/hB7-H3+ B78 than the non-targeted [89Zr]Zr-Df-bsAb CTRL control. [89Zr]Zr-Df-DINU displayed similar uptake in both GD2+ tumor models, with uptake comparable to [89Zr]Zr-Df-INV34-6 in the GD2+/hB7-H3+ B78 model. Conclusion: The GD2-B7-H3 targeting bispecific antibodies successfully improved selectivity to cells expressing both antigens. This approach should address the severe toxicities associated with GD2-targeting therapies by reducing off-tumor GD2 binding in nerves. Continued improvements in bispecific antibody technologies will continue to transform the therapeutic biologics landscape.

Radionuclide tracing based in situ corrosion and mass transport monitoring of 316L stainless steel in a molten salt closed loop.

In the study, we report an in situ corrosion and mass transport monitoring method developed using a radionuclide tracing technique for the corrosion study of 316L stainless steel (316L SS) in a NaCl-MgCl2 eutectic molten salt natural circulation loop. This method involves cyclotron irradiation of a small tube section with 16 MeV protons, later welds at the hot leg of the molten salt flow loop, generating radionuclides 51Cr, 52Mn, and 56Co at the salt-alloy interface. By measuring the activity variations of these radionuclides at different sections along the loop, both the in situ monitoring of the corrosion attack depth of 316L SS and corrosion product transport and its precipitation in flowing NaCl-MgCl2 molten salt are achieved. While 316L SS is the focus of this study, the technique reported herein can be extended to other structural materials being used in a wide range of industrial applications.

[64Cu]Cu-PEG-FUD peptide for noninvasive and sensitive detection of murine pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease resulting in irreversible scarring within the lungs. However, the lack of biomarkers that enable real-time assessment of disease activity remains a challenge in providing efficient clinical decision-making and optimal patient care in IPF. Fibronectin (FN) is highly expressed in fibroblastic foci of the IPF lung where active extracellular matrix (ECM) deposition occurs. Functional upstream domain (FUD) tightly binds the N-terminal 70-kilodalton domain of FN that is crucial for FN assembly. In this study, we first demonstrate the capacity of PEGylated FUD (PEG-FUD) to target FN deposition in human IPF tissue ex vivo. We subsequently radiolabeled PEG-FUD with 64Cu and monitored its spatiotemporal biodistribution via µPET/CT imaging in mice using the bleomycin-induced model of pulmonary injury and fibrosis. We demonstrated [64Cu]Cu-PEG-FUD uptake 3 and 11 days following bleomycin treatment, suggesting that radiolabeled PEG-FUD holds promise as an imaging probe in aiding the assessment of fibrotic lung disease activity.

Preclinical development of novel PD-L1 tracers and first-in-human study of [68Ga]Ga-NOTA-RW102 in patients with lung cancers.

BACKGROUND: The programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells' immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors' immunotherapy landscape. METHODS: By immunizing an alpaca with recombinant human PD-L1, three clones of the variable domain of the heavy chain of heavy-chain only antibody (VHH) were screened, and RW102 with high binding affinity was selected for further studies. ABDRW102, a VHH derivative, was further engineered by fusing RW102 with the albumin binder ABD035. Based on the two targeting vectors, four PD-L1-specific tracers ([68Ga]Ga-NOTA-RW102, [68Ga]Ga-NOTA-ABDRW102, [64Cu]Cu-NOTA-ABDRW102, and [89Zr]Zr-DFO-ABDRW102) with different circulation times were developed. The diagnostic efficacies were thoroughly evaluated in preclinical solid tumor models, followed by a first-in-human translational investigation of [68Ga]Ga-NOTA-RW102 in patients with non-small cell lung cancer (NSCLC). RESULTS: While RW102 has a high binding affinity to PD-L1 with an excellent KD value of 15.29 pM, ABDRW102 simultaneously binds to human PD-L1 and human serum albumin with an excellent KD value of 3.71 pM and 3.38 pM, respectively. Radiotracers derived from RW102 and ABDRW102 have different in vivo circulation times. In preclinical studies, [68Ga]Ga-NOTA-RW102 immunoPET imaging allowed same-day annotation of differential PD-L1 expression with specificity, while [64Cu]Cu-NOTA-ABDRW102 and [89Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization of PD-L1. More importantly, a pilot clinical trial shows the safety and diagnostic value of [68Ga]Ga-NOTA-RW102 immunoPET imaging in patients with NSCLCs and its potential to predict immune-related adverse effects following PD-L1-targeted immunotherapies. CONCLUSIONS: We developed and validated a series of PD-L1-targeted tracers. Initial preclinical and clinical evidence indicates that immunoPET imaging with [68Ga]Ga-NOTA-RW102 holds promise in visualizing differential PD-L1 expression, selecting patients for PD-L1-targeted immunotherapies, and monitoring immune-related adverse effects in patients receiving PD-L1-targeted treatments. TRIAL REGISTRATION NUMBER: NCT06165874.

Development of an Engineered Single-Domain Antibody for Targeting MET in Non-Small Cell Lung Cancer.

The Mesenchymal Epithelial Transition (MET) receptor tyrosine kinase is upregulated or mutated in 5% of non-small-cell lung cancer (NSCLC) patients and overexpressed in multiple other cancers. We sought to develop a novel single-domain camelid antibody with high affinity for MET that could be used to deliver conjugated payloads to MET expressing cancers. From a naïve camelid variable-heavy-heavy (VHH) domain phage display library, we identified a VHH clone termed 1E7 that displayed high affinity for human MET and was cross-reactive with MET across multiple species. When expressed as a bivalent human Fc fusion protein, 1E7-Fc was found to selectively bind to EBC-1 (MET amplified) and UW-Lung 21 (MET exon 14 mutated) cell lines by flow cytometry and immunofluorescence imaging. Next, we investigated the ability of [89Zr]Zr-1E7-Fc to detect MET expression in vivo by PET/CT imaging. [89Zr]Zr-1E7-Fc demonstrated rapid localization and high tumor uptake in both xenografts with a %ID/g of 6.4 and 5.8 for EBC-1 and UW-Lung 21 at 24 h, respectively. At the 24 h time point, clearance from secondary and nontarget tissues was also observed. Altogether, our data suggest that 1E7-Fc represents a platform technology that can be employed to potentially both image and treat MET-altered NSCLC.

"Off-Label Use" of the Siderophore Enterobactin Enables Targeted Imaging of Cancer with Radioactive Ti(IV).

The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide 45Ti for radiopharmaceutical applications. Herein, we evaluate the Ti(IV)-coordination chemistry of four catechol-based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN-CAM readily form mononuclear Ti(IV) species in aqueous solution at neutral pH. Radiolabeling studies reveal that Ent and TREN-CAM form mononuclear complexes with the short-lived, positron-emitting radionuclide 45Ti(IV), and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in naïve mice. These features guide efforts to target the 45Ti isotope to prostate cancer tissue through the design, synthesis, and evaluation of Ent-DUPA, a small molecule conjugate composed of a prostate specific membrane antigen (PSMA) targeting peptide and a monofunctionalized Ent scaffold. The [45Ti][Ti(Ent-DUPA)]2- complex forms readily at room temperature. In a tumor xenograft model in mice, selective tumor tissue accumulation (8±5 %, n=5), and low off-target uptake in other organs is observed. Overall, this work demonstrates targeted imaging with 45Ti(IV), provides a foundation for advancing the application of 45Ti in nuclear medicine, and reveals that Ent can be repurposed as a 45Ti-complexing cargo for targeted nuclear imaging applications.

Noninvasive PET imaging of tumor PD-L1 expression with 64Cu-labeled Durvalumab.

Breast cancer (BrCa) ranks as the most prevalent malignant neoplasm affecting women worldwide. The expression of programmed death-ligand 1 (PD-L1) in BrCa has recently emerged as a biomarker for immunotherapy response, but traditional immunohistochemistry (IHC)-based methods are hindered by spatial and temporal heterogeneity. Noninvasive and quantitative PD-L1 imaging using appropriate radiotracers can serve to determine PD-L1 expression in tumors. This study aims to demonstrate the viability of PET imaging with 64Cu-labeled Durvalumab (abbreviated as Durva) to assess PD-L1 expression using a murine xenograft model of breast cancer. Durvalumab, a human IgG1 monoclonal antibody against PD-L1, was assessed for specificity in vitro in two cancer cell lines (MDA-MB-231 triple-negative breast cancer cell line and AsPC-1 pancreatic cancer cell line) with positive and negative PD-L1 expression by flow cytometry. Next, we performed the in vivo evaluation of 64Cu-NOTA-Durva in murine models of human breast cancer by PET imaging and ex vivo biodistribution. Additionally, mice bearing AsPC-1 tumors were employed as a negative control. Tumor uptake was quantified based on a 3D region-of-interest (ROI) analysis of the PET images and ex vivo biodistribution measurements, and the results were compared against conventional IHC testing. The radiotracer uptake was evident in MDA-MB-231 tumors and showed minimal nonspecific binding, corroborating IHC-derived results. The results of the biodistribution showed that the MDA-MB-231 tumor uptake of 64Cu-NOTA-Durva was much higher than 64Cu-NOTA-IgG (a nonspecific radiolabeled IgG). In Conclusion, 64Cu-labeled Durvalumab PET/CT imaging offers a promising, noninvasive approach to evaluate tumor PD-L1 expression.

Radiolabeling Diaminosarcophagine with Cyclotron-Produced Cobalt-55 and [55Co]Co-NT-Sarcage as a Proof of Concept in a Murine Xenograft Model.

Cobalt-sarcophagine complexes exhibit high kinetic inertness under various stringent conditions, but there is limited literature on radiolabeling and in vivo positron emission tomography (PET) imaging using no carrier added 55Co. To fill this gap, this study first investigates the radiolabeling of DiAmSar (DSar) with 55Co, followed by stability evaluation in human serum and EDTA, pharmacokinetics in mice, and a direct comparison with [55Co]CoCl2 to assess differences in pharmacokinetics. Furthermore, the radiolabeling process was successfully used to generate the NTSR1-targeted PET agent [55Co]Co-NT-Sarcage (a DSar-functionalized SR142948 derivative) and administered to HT29 tumor xenografted mice. The [55Co]Co-DSar complex can be formed at 37 °C with purity and stability suitable for preclinical in vivo radiopharmaceutical applications, and [55Co]Co-NT-Sarcage demonstrated prominent tumor uptake with a low background signal. In a direct comparison with [64Cu]Cu-NT-Sarcage, [55Co]Co-NT-Sarcage achieved a higher tumor-to-liver ratio but with overall similar biodistribution profile. These results demonstrate that Sar would be a promising chelator for constructing Co-based radiopharmaceuticals including 55Co for PET and 58mCo for therapeutic applications.

Amplification of Cerenkov luminescence using semiconducting polymers for cancer theranostics.

The therapeutic efficacy of photodynamic therapy is limited by the ability of light to penetrate tissues. Due to this limitation, Cerenkov luminescence (CL) from radionuclides has recently been proposed as an alternative light source in a strategy referred to as Cerenkov radiation induced therapy (CRIT). Semiconducting polymer nanoparticles (SPNs) have ideal optical properties, such as large absorption cross-sections and broad absorbance, which can be utilized to harness the relatively weak CL produced by radionuclides. SPNs can be doped with photosensitizers and have nearly 100% energy transfer efficiency by multiple energy transfer mechanisms. Herein, we investigated an optimized photosensitizer doped SPN as a nanosystem to harness and amplify CL for cancer theranostics. We found that semiconducting polymers significantly amplified CL energy transfer efficiency. Bimodal PET and optical imaging studies showed high tumor uptake and retention of the optimized SPNs when administered intravenously or intratumorally. Lastly, we found that photosensitizer doped SPNs have excellent potential as a cancer theranostics nanosystem in an in vivo tumor therapy study. Our study shows that SPNs are ideally suited to harness and amplify CL for cancer theranostics, which may provide a significant advancement for CRIT that are unabated by tissue penetration limits.

Separation of cyclotron-produced cobalt-55/58m from iron targets using cation exchange chromatography with non-aqueous solvents and extraction chromatography.

Cobalt-55 and -58m form a theranostic pair that has relevant properties for cancer research. We report a cation exchange chromatography/extraction chromatography method that separates cyclotron-produced 55/58mCo from 54/57Fe in <1.5 h, recovers >85% Co and achieves [55Co]Co-NOTA and -DOTA AMA 89 ± 48 and 35 ± 7 MBq/nmol (EOB), respectively. Cobalt-55 and -58m were quantitatively labeled to functionalized NOTA at 106 and 50 MBq/nmol (EOB), respectively, corroborating measured AMA. This method is faster than previously published methods and achieves better [55/58mCo]Co-NOTA and -DOTA AMA.

Correction: Radiolabeling and in vivo evaluation of lanmodulin with biomedically relevant lanthanide isotopes.

[This corrects the article DOI: 10.1039/D3CB00020F.].

Recycling of 52Cr electroplated targets for 52gMn production.

52gMn is a promising radionuclide for positron emission tomography (PET). Enriched 52Cr targets are required to minimize formation of 54Mn radioisotopic impurities during production with proton beams. The need for radioisotopically pure 52gMn, accessibility and cost of 52Cr, sustainability of the radiochemical process, and potential for iterative purification of target materials motivate this development of recyclable, electroplated 52Cr metal targets and radiochemical isolation and labeling with resulting >99.89% radionuclidically pure 52gMn. The run-to-run replating efficiency is 60 ± 20%, and unplated chromium from this method is recovered with 94% efficiency as 52CrCl3 hexahydrate. The decay-corrected molar activity of chemically isolated 52gMn for common chelating ligands was 376 MBq/µmol.

De Novo Approaches to the Solid-Phase Separation of Titanium(IV) and Scandium(III): Translating Speciation Data to Selective On-Bead Chelation toward Applications in Nuclear Medicine.

The solution chemistry of the hydrolytic, early-transition-metal ions Ti4+ and Sc3+ represents a coordination chemistry challenge with important real-world implications, specifically in the context of 44Ti/44Sc and 45Ti/NatSc radiochemical separations. Unclear speciation of the solid and solution phases and tertiary mixtures of mineral acid, organic chelators, and solid supports are common confounds, necessitating tedious screening of multiple variables. Herein we describe how thermodynamic speciation data in solution informs the design of new solid-phase chelation approaches enabling separations of Ti4+ and Sc3+. The ligands catechol (benzene-1,2-diol) and deferiprone [3-hydroxy-1,2-dimethyl-4(1H)-pyridone] bind Ti4+ at significantly more acidic conditions (2-4 pH units) than Sc3+. Four chelating resins were synthesized using either catechol or deferiprone with two different solid supports. Of these, deferiprone appended to carboxylic acid polymer-functionalized silica (CA-Def) resin exhibited excellent binding affinity for Ti4+ across a wide range of HCl concentrations (1.0-0.001 M), whereas Sc3+ was only retained in dilute acidic conditions (0.01-0.001 M HCl). CA-Def resin produced separation factors of >100 (Ti/Sc) in 0.1-0.4 M HCl, and the corresponding Kd values (>1000) show strong retention of Ti4+. A model 44Ti/44Sc generator was produced, showing 65 ± 3% yield of 44Sc in 200 µL of 0.2 M HCl with a significant 44Ti breakthrough of 0.1%, precluding use in its current form. Attempts, however, removed natSc in loading fractions and a dilute (0.4 M HCl) wash and recovered 80% of the loaded 45Ti activity in 400 µL of 6 M HCl. The previously validated 45Ti chelator TREN-CAM was used for comparative proof-of-concept reactions with the CA-Def eluent (in HCl) and literature-reported hydroxamate-based resin eluents (in citric acid). CA-Def shows improved radiolabeling efficiency with an apparent molar activity (AMA) of 0.177 mCi nmol-1, exceeding the established methods (0.026 mCi nmol-1) and improving the separation and recovery of 45Ti for positron emission tomography imaging applications.

Production and radiochemistry of antimony-120m: Efforts toward Auger electron therapy with 119Sb.

Targeted Meitner-Auger Therapy (TMAT) has potential for personalized treatment thanks to its subcellular dosimetric selectivity, which is distinct from the dosimetry of ß- and α particle emission based Targeted Radionuclide Therapy (TRT). To date, most clinical and preclinical TMAT studies have used commercially available radionuclides. These studies showed promising results despite using radionuclides with theoretically suboptimal photon to electron ratios, decay kinetics, and electron emission spectra. Studies using radionuclides whose decay characteristics are considered more optimal are therefore important for evaluation of the full potential of Meitner-Auger therapy; 119Sb is among the best such candidates. In the present work, we develop radiochemical purification of 120Sb from irradiated natural tin targets for TMAT studies with 119Sb.