The fibronectin-targeting PEG-FUD imaging probe shows enhanced uptake during fibrogenesis in experimental lung fibrosis.

Progressive forms of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF), are deadly disorders lacking non-invasive biomarkers for assessment of early disease activity, which presents a major obstacle in disease management. Excessive extracellular matrix (ECM) deposition is a hallmark of these disorders, with fibronectin being an abundant ECM glycoprotein that is highly upregulated in early fibrosis and serves as a scaffold for the deposition of other matrix proteins. Due to its role in active fibrosis, we are targeting fibronectin as a biomarker of early lung fibrosis disease activity via the PEGylated fibronectin-binding polypeptide (PEG-FUD).

Rapid fabrication and dissolution of pressed Ni/Mg matrix targets for Co production.

Background: Beyond the use of conventional short-lived PET radionuclides, there is a growing interest in tracking larger biomolecules and exploring radiotheranostic applications. One promising option for imaging medium-sized molecules and peptides is ⁵⁵Co (T₁/₂ = 17.5 h, β⁺ = 76%), which enables imaging of new and already established tracers with blood circulation of several hours.

Measurement of the Ge(d,n)As cross section from 2.1 MeV to 10 MeV.

This work reports experimental Ge(d,n)As cross sections producing Arsenic-71 (t = 65.3 h, 28% β), a potentially useful diagnostic radionuclide. Target stacks containing two Ge foils, a Ni monitor foil, and an Al degrader were irradiated with 5.

Solid phase extraction chromatography-based radiochemical isolation of cyclotron-produced Mn from enriched Fe targets.

We report DGA extraction chromatography isolation of Mn from isotopically enriched Fe. The method has been studied in semi-automated and automated realizations. The former achieves a decay corrected radiochemical yield of 78 ± 1 % (n = 3) and a separation factor of (1.

Phosphonate-Based Aza-Macrocycle Ligands for Low-Temperature, Stable Chelation of Medicinally Relevant Rare Earth Radiometals and Radiofluorination.

Radioisotopes of fluorine (F), scandium (Sc, Sc), lutetium (Lu), and yttrium (Y, Y) have decay properties ideally suited for targeted nuclear imaging and therapy with small biologics, such as peptides and antibody fragments. However, a single-molecule strategy to introduce these radionuclides into radiopharmaceuticals under mild conditions to afford inert in vivo complexes is critically lacking. Here, we introduce HL2 and HL3, two small-cavity macrocyclic chelator structural isomers bearing a single phosphonate functional group.

Immuno-PET Imaging of CD93 Expression with Cu-Radiolabeled NOTA-mCD93 ([Cu]Cu-NOTA-mCD93) and Insulin-Like Growth Factor Binding Protein 7 ([Cu]Cu-NOTA-IGFBP7).

CD93 is overexpressed in multiple solid tumor types, serving as a novel target for antiangiogenic therapy. The goal of this study was to develop a Cu-based positron emission tomography (PET) tracer for noninvasive imaging of CD93 expression. Antimouse-CD93 mAb (mCD93) and the CD93 ligand IGFBP7 were conjugated to a bifunctional chelator, -isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid (-SCN-NOTA) and labeled with Cu.

Sustainable production of radionuclidically pure antimony-119.

Background: Radiopharmaceutical therapy (RPT) uses radionuclides that decay via one of three therapeutically relevant decay modes (alpha, beta, and internal conversion (IC) / Auger electron (AE) emission) to deliver short range, highly damaging radiation inside of diseased cells, maintaining localized dose distribution and sparing healthy cells. Antimony-119 (Sb, t = 38.19 h, EC = 100%) is one such IC/AE emitting radionuclide, previously limited to in silico computational investigation due to barriers in production, chemical separation, and chelation.

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

The widely established PET isotope F 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 F as diagnostic partners to Sc and Lu radiotherapeutics. Here, we synthesized a library of tacn-based chelators comprised of 10 structurally unique permutations incorporating acetate, methyl-benzylamide and picolinate donor arms.

Radiochemistry and Complex Formation of the Cyclen-Derived Chelator DOTI-Me with Mn, Cu, Zn, Ga, In, Tb, and Lu.

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 Mn, Cu, Ga, In, Tb, and Lu, and DOTI-Me showed distinct differences to the structurally related HDOTA. While radiochemical conversions (RCCs) for Mn and In were comparable to those of HDOTA, DOTI-Me was not suited for Ga.

Controlling the Redox Chemistry of Cobalt Radiopharmaceuticals.

The elementally matched Co (t=17.53 h, I=77 %)/Co (t=9.10 h, internal conversion=100 %) radioisotope pair is of interest for development of paired diagnostic/therapeutic radiopharmaceuticals.

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.

Synthesis of Cu-, Co-, and Ga-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.

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.

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-MgCl 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 Cr, Mn, and Co 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-MgCl molten salt are achieved.

[Cu]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.

Preclinical development of novel PD-L1 tracers and first-in-human study of [Ga]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.

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

Construction of the Bioconjugate Py-Macrodipa-PSMA and Its In Vivo Investigations with Large La and Small Sc Radiometal Ions.

To harness radiometals in clinical settings, a chelator forming a stable complex with the metal of interest and targets the desired pathological site is needed. Toward this goal, we previously reported a unique set of chelators that can stably bind to both large and small metal ions, via a conformational switch. Within this chelator class, py-macrodipa is particularly promising based on its ability to stably bind several medicinally valuable radiometals including large La, Bi, and small Sc.

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.

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

The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide Ti for radiopharmaceutical applications. Herein, we evaluate the Ti-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 species in aqueous solution at neutral pH.

Radiolabeling Diaminosarcophagine with Cyclotron-Produced Cobalt-55 and [Co]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 Co. To fill this gap, this study first investigates the radiolabeling of DiAmSar (DSar) with Co, followed by stability evaluation in human serum and EDTA, pharmacokinetics in mice, and a direct comparison with [Co]CoCl to assess differences in pharmacokinetics. Furthermore, the radiolabeling process was successfully used to generate the NTSR1-targeted PET agent [Co]Co-NT-Sarcage (a DSar-functionalized SR142948 derivative) and administered to HT29 tumor xenografted mice.

Measurement of synaptic density in Down syndrome using PET imaging: a pilot study.

Down syndrome (DS) is the most prevalent genetic cause of intellectual disability, resulting from trisomy 21. Recently, positron emission tomography (PET) imaging has been used to image synapses in vivo. The motivation for this pilot study was to investigate whether synaptic density in low functioning adults with DS can be evaluated using the PET radiotracer [C]UCB-J.

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.

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 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-MgCl eutectic molten salt natural circulation loop. This novel method involved cyclotron irradiation of a small tube section with 16 MeV protons, later welded at the hot leg of the molten salt flow loop, generating radionuclides , , and at the salt-alloy interface. By measuring the activity variations of these radionuclides at different sections along the loop, both the monitoring of the corrosion attack depth of 316L SS and corrosion product transport and its precipitation in flowing NaCl-MgCl molten salt were achieved.