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At least 109 records · Page 6

Titanium-45 (45Ti) Radiochemistry and Applications in Molecular Imaging

Molecular imaging is an important part of modern medicine which enables the non-invasive identification and characterization of diseases. With the advancement of radiochemistry and scanner technology, nuclear medicine is providing insight into efficient treatment options for individual patients. Titanium-45 (45Ti) is a lesser-explored radionuclide that is garnering increasing interest for the development of positron emission tomography (PET) radiopharmaceuticals. This review discusses aspects of this radionuclide including production, purification, radiochemistry development, and molecular imaging studies.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

PET Imaging of the Neurotensin Targeting Peptide NOTA-NT-20.3 Using Cobalt-55, Copper-64 and Gallium-68

Introduction: Neurotensin receptor 1 (NTSR1) is an emerging target for imaging and therapy of many types of cancer. Nuclear imaging of NTSR1 allows for noninvasive assessment of the receptor levels of NTSR1 on the primary tumor, as well as potential metastases. This work focuses on a the neurotensin peptide analogue NT-20.3 conjugated to the chelator NOTA for radiolabeling for use in noninvasive positron emission tomography (PET). NOTA-NT-20.3 was radiolabeled with gallium-68, copper-64, and cobalt-55 to determine the effect that modification of the radiometal has on imaging and potential therapeutic properties of NOTA-NT-20.3. Methods: In vitro assays investigating cell uptake and subcellular localization of the radiolabeled peptides were performed using human colorectal adenocarcinoma HT29 cells. In vivo PET/CT imaging was used to determine the distribution and clearance of the peptide in mice bearing NTSR1 expressing HT29 tumors. Results: Cell uptake studies showed that the highest uptake was obtained with [ 55 Co] Co-NOTA-NT-20.3 (18.70 ± 1.30%ID/mg), followed by [ 64 Cu] Cu-NOTA-NT-20.3 (15.46 ± 0.91%ID/mg), and lastly [ 68 Ga] Ga-NOTA-NT-20.3 (10.94 ± 0.46%ID/mg) (p < 0.001). Subcellular distribution was similar across the three constructs, with the membranous fraction containing the highest amount of radioactivity. In vivo PET/CT imaging of the three constructs revealed similar distribution and tumor uptake at the 1 h imaging timepoint. Tumor uptake was receptor-specific and blockable by co-injection of non-radiolabeled NOTA-NT-20.3. SUV ratios of tumor to heart at the 24 h imaging timepoint show that [ 55 Co] Co-NOTA-NT-20.3 (20.28 ± 3.04) outperformed [ 64 Cu] Cu-NOTA-NT-20.3 (6.52 ± 1.97). In conclusion, our studies show that enhanced cell uptake and increasing tumor to blood ratios over time displayed the superiority of [ 55 Co] Co-NOTA-NT-20.3 over [ 68 Ga] Ga-NOTA-NT-20.3 and [ 64 Cu] Cu-NOTA-NT-20.3 for the targeting of NTSR1.

60 APPLIED LIFE SCIENCES↗

Synthesis of fluorinated radiopharmaceuticals via electrochemical fluorination

Provided herein are methods and compositions for the electrochemical selective radiofluorination of aromatic molecules. The resulting fluorine-18 labeled compounds are ideal radionuclides for use in Positron Emission Tomography (PET); they are also difficult to radiolabel efficiently and with high specific activity using existing approaches. For example, radiopharmaceuticals such as [F18]L-DOPA, which is indispensable in PET brain disease imaging, may be made electrochemically with high radiochemical yield and high specific activity using 18F-. The invention process described herein opens new possibilities and provides wider access to PET tracers such as 18F-L-Dopa, since 18F- is much more widely available than the 18F2, currently used for synthesis of electron rich substrates.

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEA↗

Production of Medically Desirable Radioisotopes in the EIRENE Molten Salt Reactor

Radioisotopes play a vital role in nuclear medicine, enabling the performance of diagnostic procedures such as Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT), in addition to innovative targeted therapies for selectively delivering cytotoxic radiation doses to tumor cells while minimizing damage to healthy tissue [1]. Beta emitting radionuclides such as 90Y and 131I find wide use in radio-immunotherapy, with the radiopharmaceuticals 90Y-ibritumomab tiuxetan (Zevalin®) and 131I-tositumomab (Bexxar®) having received FDA approval for treatment of non-Hodgkin’s lymphoma through targeting the CD20 surface receptor, which is commonly expressed in many B cell non-Hodgkin’s lymphoma subtypes [2, 3]. 90Y has also been successfully applied for treatment of brain tumors [4, 5] and liver cancer [6]. The favorable chelation chemistry of 90Y enables its use with a variety of ligands for the development of radiopharmaceuticals suitable for targeting different carcinoma types [1].

42 - ENGINEERING↗

Gamma Ray Detection In Liquid Argon Time Projection Chambers

Gamma rays are photons in excess of 100 keV of energy and can be produced by a variety of mechanisms like radioactive decay and inelastic neutrino-argon interactions. A reconstruc- tion of Compton scattering gamma rays was developed for use in liquid argon time projection chambers. This reconstruction was tested with detectors developed to demonstrate the ca- pabilities of Deep Underground Neutrino Experiment (DUNE) Near Detector Liquid Argon target (ND LAr). In October 2024, a radioactive fluorine-18 source was placed next to the Full Scale Demonstrator. The data obtained was used to test this reconstruction algorithm. It was able to determine the direction of the photons with an error of less than 10 percent. In addition to this work, there has been significant work on designing a liquid argon based Positron Emission Tomography (PET) scanner. PET scanners detect gamma rays emitted by a tracer chemical to help screen for diseases like cancer. In addition to the applications to medical imaging, this thesis briefly explores the applications of this reconstruction to de-excitation photons produced in interactions between neutrinos and argon nuclei. These applications could improve studies focusing on neutrinos originating from accelerators and supernovae.

Murphy, Thomas [Syracuse U.]↗

Evaluation of 134 Ce as a PET imaging surrogate for antibody drug conjugates incorporating 225 Ac

The in vivo generator 134 Ce/ 134 La has the potential to serve as a PET imaging surrogate for both alpha-emitting 225 Ac and 227 Th radionuclides due to the unique Ce III /Ce IV redox couple and the relatively long half-life of 134 Ce. Furthermore, the purpose of this study was to demonstrate the compatibility of 134 Ce with DOTA-based antibody drug conjugates, which would act as therapeutic agents when incorporating 225 Ac.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Preliminary investigation of 48 V-labeled VO(acac) 2 for cancer imaging: An initial proof-of-concept study

In this preliminary study, a procedure for synthesizing novel PET radiotracer vanadium-48-labeled-vanadyl acetylacetonate was developed, including radioisotope production via cyclotron, separation of 48 V, chelation as 48 VO(acac) 2 , and assessment through in vitro cellular studies. We employed the beam-stop setup in a cyclotron as the target holder to irradiate titanium foils in the reaction of nat Ti (p,n) 48 V. The radioisotope production rate was 4.84 ± 0.67 μCi/μA-h. Overall radiochemical yield was 12.86 ± 0.51% with gamma-ray spectroscopy showing no detectable contaminant peaks. HPLC of 48 VO(acac) 2 showed a retention time (1:48) corresponding closely to that (1:50) of commercial VO(acac) 2 , verifying the successful synthesis of 8VO(acac) 2 . In vitro cellular studies demonstrated radiotracer uptake and saturation around 0.48 nM. These studies pave the way for improving methodologies and in vivo experiments, including imaging studies, in future investigations.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Measurement of the 70 Ge( d , n ) 71 As cross section from 2.1 MeV to 10 MeV

This work reports experimental 70 Ge(d,n) 71 As cross sections producing Arsenic-71 (t 1/2 = 65.3 h, 28% β + ), a potentially useful diagnostic radionuclide. Target stacks containing two nat Ge foils, a nat Ni monitor foil, and an Al degrader were irradiated with 5.5–10 MeV deuterons using an FN Tandem Van de Graaff accelerator. 71 As and 61 Cu, 56 Co, and 58 Co (from nat Ni(d,x)) were quantified in the foils by high purity germanium gamma spectrometry. Furthermore, the measured cross sections are larger than previously reported and suitable for producing preclinical quantities of diagnostic radiopharmaceuticals.

07 ISOTOPE AND RADIATION SOURCES↗

Low-dose high-resolution $\mathrm{TOF}$-$\mathrm{PET}$ using ionization-activated multi-state low-$\mathrm{Z}$ detector media

We propose PET scanners using low atomic number media that undergo a persistent local change of state along the paths of the Compton recoil electrons. Measurement of the individual scattering locations and angles, deposited energies, and recoil electron directions allows using the kinematical constraints of the 2-body Compton scattering process to perform a statistical time-ordering of the scatterings, with a high probability of precisely identifying where the gamma first interacted in the detector. In these cases the Line-of-Response is measured with high resolution, determined by the underlying physics processes and not the detector segmentation. There are multiple such media that act through different mechanisms. As an example in which the change of state is quantum-mechanical through a change in molecular configuration, rather than thermodynamic, as in a bubble chamber, we present simulations of a two-state photoswitchable organic dye, a ‘Switchillator’, that is activated to a fluorescent-capable state by the ionization of the recoil electrons. The activated state is persistent, and can be optically excited multiple times to image individual activated molecules. Energy resolution is provided by counting the activated molecules. Location along the LOR is implemented by large-area time-of-flight MCP-PMT photodetectors with single photon time resolution in the tens of ps and sub-mm spatial resolution. Simulations indicate a large reduction of dose.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

Excitation function of 54 Fe(p, α ) 51 Mn from 9.5 MeV to 18 MeV

Excitation function of the 54 Fe(p,α) 51 Mn reaction was measured from 9.5 to 18 MeV $E_{0,p^+}$ by activating a foil stack of 54 Fe electrodeposited on copper substrates. Residual radionuclides were quantified by HPGe gamma ray spectrometry. Both 51 Mn ($t_{1/2}$ = 46.2 min, $\langle E_{β^+}\rangle$=963.7keV, $I_{β^+}$ = 97%; $E_γ$ = 749.1keV, $I_γ$ = 0.265%) and its radioactive daughter, 51 Cr ($t_{1/2}$ = 27.704d, $E_γ$ = 320.1 keV, $I_γ$ = 9.91%), were used to indirectly quantify formation of 51 Mn. Results agree within uncertainty to the only other measurement in literature and predictions of default TALYS theoretical code. Final relative uncertainties are within ±12%.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗

Preclinical studies of a PARP targeted, Meitner-Auger emitting, theranostic radiopharmaceutical for metastatic ovarian cancer

Advanced ovarian cancer currently has few therapeutic options. Poly(ADP-ribose) polymerase (PARP) inhibitors bind to nuclear PARP and trap the protein-inhibitor complex to DNA. This work investigates a theranostic PARP inhibitor for targeted radiopharmaceutical therapy of ovarian cancer in vitro and PET imaging of healthy mice in vivo. Methods: [ 77 Br]RD1 was synthesized and assessed for pharmacokinetics and cytotoxicity in human and murine ovarian cancer cell lines. [ 76 Br]RD1 biodistribution and organ uptake in healthy mice were quantified through longitudinal PET/CT imaging and ex vivo radioactivity measurements. Organ-level dosimetry following [ 76/77 Br]RD1 administration was calculated using RAPID, an in-house platform for absorbed dose in mice, and OLINDA for equivalent and effective dose in human. Results: The maximum specific binding (B max ), equilibrium dissociation constant (K d ), and nonspecific binding slope (NS) were calculated for each cell line. These values were used to calculate the cell specific activity uptake for cell viability studies. The half maximal effective concentration (EC 50 ) was measured as 0.17 (95 % CI: 0.13–0.24) nM and 0.46 (0.13–0.24) nM for PARP(+) and PARP(–) expressing cell lines, respectively. The EC 50 was 0.27 (0.21–0.36) nM and 0.30 (0.22–0.41) nM for BRCA1(–) and BRCA1(+) expressing cell lines, respectively. When measuring the EC 50 as a function of cellular activity uptake and nuclear dose, the EC 50 ranges from 0.020 to 0.039 Bq/cell and 3.3–9.2 Gy, respectively. Excretion through the hepatobiliary and renal pathways were observed in mice, with liver uptake of 2.3 ± 0.4 %ID/g after 48 h, contributing to estimated absorbed dose values in mice of 19.3 ± 0.3 mGy/MBq and 290 ± 10 mGy/MBq for [ 77 Br]RD1 and [ 76 Br]RD1, respectively. Conclusion: [ 77 Br]RD1 cytotoxicity was dependent on PARP expression and independent of BRCA1 status. Finally, the in vitro results suggest that [ 77 Br]RD1 cytotoxicity is driven by the targeted Meitner-Auger electron (MAe) radiotherapeutic effect of the agent. Further studies investigating the theranostic potential, organ dose, and tumor uptake of [ 76/77 Br]RD1 are warranted.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Mechanisms of Polyethylene Terephthalate Pellet Fragmentation into Nanoplastics and Assimilable Carbons by Wastewater Comamonas

Comamonadaceae bacteria are enriched on poly(ethylene terephthalate) (PET) microplastics in wastewaters and urban rivers, but the PET-degrading mechanisms remain unclear. Here, we investigated these mechanisms with Comamonas testosteroniKF-1, a wastewater isolate, by combining microscopy, spectroscopy, proteomics, protein modeling, and genetic engineering. Compared to minor dents on PET films, scanning electron microscopy revealed significant fragmentation of PET pellets, resulting in a 3.5-fold increase in the abundance of small nanoparticles (<100 nm) during 30-day cultivation. Infrared spectroscopy captured primarily hydrolytic cleavage in the fragmented pellet particles. Solution analysis further demonstrated double hydrolysis of a PET oligomer, bis(2-hydroxyethyl) terephthalate, to the bioavailable monomer terephthalate. Supplementation with acetate, a common wastewater co-substrate, promoted cell growth and PET fragmentation. Of the multiple hydrolases encoded in the genome, intracellular proteomics detected only one, which was found in both acetate-only and PET-only conditions. Homology modeling of this hydrolase structure illustrated substrate binding analogous to reported PET hydrolases, despite dissimilar sequences. Mutants lacking this hydrolase gene were incapable of PET oligomer hydrolysis and had a 21% decrease in PET fragmentation; re-insertion of the gene restored both functions. Thus, we have identified constitutive production of a key PET-degrading hydrolase in wastewater Comamonas, which could be exploited for plastic bioconversion.

54 ENVIRONMENTAL SCIENCES↗

Multilayer Chitin–Chitosan–Cellulose Barrier Coatings on Poly(ethylene terephthalate)

Currently, effective barrier properties over a wide range of humidity are achieved by layering multiple plastics, resulting in structures that are nearly impossible to recycle through current systems. There is strong interest in developing barriers that are recyclable, biodegradable, or compostable. Chitin and cellulose nanomaterials are promising alternatives because of their high crystallinity, renewable sourcing, strong electrostatic interactions, and potential for biodegradation or composting. In this paper, we explore the potential to create multilayer materials with effective oxygen and water vapor barrier properties at elevated humidity by combining recyclable poly(ethylene terephthalate) (PET) films with single-layer and bilayer coatings of chitin nanowhiskers (ChNWs), chitosan (CS), and cellulose nanocrystals (CNCs). The addition of CS to the ChNW suspension improved the gas barrier properties of ChNW coatings, likely by filling voids, and short ChNWs (SChNW, 114 nm) performed better than long ChNWs (LChNW, 230 nm). At the optimal mass ratio of 1:1 SChNW/CS, the oxygen permeability (OP) of SChNW/CS-coated PET films was 5.1 cm 3 μm m –2 day –1 kPa –1 versus 15.9 cm 3 μm m –2 day –1 kPa –1 for neat PET. To take advantage of electrostatic attraction and hydrogen bonding, CNC was first coated on the PET, followed by coating with ChNW/CS, resulting in an OP as low as 3.6 cm 3 μm m –2 day –1 kPa –1 at 50% relative humidity (RH), and 6.4 cm 3 μm m –2 day –1 kPa –1 at 80% RH. Furthermore, after thermal treatment (120 °C, 2.5 h), the OP dropped to 2.2 cm 3 μm m –2 day –1 kPa –1 (50% RH) and 4.8 cm 3 μm m –2 day –1 kPa –1 (80% RH). The ChNW/CS and CNC coating can be efficiently removed with alkali treatment enabling possible recycling of the coated PET films.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Diagnostic, Prognostic, and Therapeutic Use of Radiopharmaceuticals in the Context of SARS-CoV-2

The coronavirus disease 2019 (COVID-19) outbreak has devastated the healthcare systems and economies of over 200 countries in just a few months. The etiological agent of COVID-19, SARS-CoV-2, is a highly contagious virus that can be transmitted by asymptomatic and symptomatic carriers alike. While in vitro testing techniques have allowed for population-wide screening, prognostic tools are required to assess the disease severity and therapeutic response, contributing to improve the patient clinical outcomes. Moreover, no specific antiviral against COVID-19 exists at the time of publication, severely limiting treatment against the infection. Hence, there is an urgent clinical need for innovative therapeutic strategies that may contribute to manage the COVID-19 outbreak and prevent future pandemics. In this work, we critically examine recent diagnostic, prognostic, and therapeutic advancements for COVID-19 in the field of radiopharmaceuticals. First, we summarize the gold standard techniques used to diagnose COVID-19, including in vitro assays and imaging techniques, and then discuss how radionuclide-based nuclear imaging provides complementary information for prognosis and treatment management of infected patients. Second, we introduce new emerging types of radiotherapies that employ radioimmunoconjugates, which have shown selective cytotoxic response in oncological studies, and critically analyze how these compounds could be used as therapeutic agents against SARS-CoV-2. Finally, this Perspective further discusses the emerging applications of radionuclides to study the behavior of pulmonary SARS-CoV-2 aerosol particles.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Production and purification of 43Sc and 47Sc from enriched [46Ti]TiO2 and [50Ti]TiO2 targets

Abstract The radioscandium isotopes, 43 Sc and 47 Sc, compose a promising elementally matched theranostic pair that can be used for the development of imaging and therapeutic radiopharmaceuticals with identical structures. This study aimed to investigate the production of high radionuclidic purity 43 Sc from enriched [ 46 Ti]TiO 2 targets and 47 Sc from enriched [ 50 Ti]TiO 2 targets and establish a target recycling technique. Enriched [ 46 Ti]TiO 2 targets were irradiated with 18 MeV protons, and enriched [ 50 Ti]TiO 2 targets were bombarded with 24 MeV protons. 43 Sc and 47 Sc were purified using ion chromatography attaining recovery yields of 91.7 ± 7.4% and 89.9 ± 3.9%, respectively. The average radionuclidic purity for 43 Sc was 98.8 ± 0.3% and for 47 Sc 91.5 ± 0.6%, while the average recovery of enriched titanium target material was 96 ± 4.0%. The highest apparent molar activity for [ 43 Sc]Sc-DOTA was 23.2 GBq/µmol and 3.39 GBq/µmol for [ 47 Sc]Sc-DOTA. This work demonstrates the feasibility of using enriched recycled [ 46 Ti]TiO 2 and [ 50 Ti]TiO 2 targets to produce high purity 43 Sc and 47 Sc as an elementally matched theranostic isotope pair.

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEA↗

Relevance of biomarkers across different neurodegenerative diseases

The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer’s disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field.

60 APPLIED LIFE SCIENCES↗

Engineering a modular 44 Ti/ 44 Sc generator: eluate evaluation in preclinical models and estimation of human radiation dosimetry

Background: 44 Sc/ 47 Sc is an attractive theranostic pair for targeted in vivo positron emission tomographic (PET) imaging and beta-particle treatment of cancer. The 44 Ti/ 44 Sc generator allows daily onsite production of this diagnostic isotope, which may provide an attractive alternative for PET facilities that lack in-house irradiation capabilities. Early animal and patient studies have demonstrated the utility of 44 Sc. In our current study, we built and evaluated a novel clinical-scale 44 Ti/ 44 Sc generator, explored the pharmacokinetic profiles of 44 ScCl 3 , [ 44 Sc]-citrate and [ 44 Sc]-NODAGA (1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid) in naïve mice, and estimated the radiation burden of 44 ScCl 3 in humans. Methods: 44 Ti/ 44 Sc (101.2 MBq) in 6 M HCl solution was utilized to assemble a modular ZR resin containing generator. After assembly, 44 Sc was eluted with 0.05 M HCl for further PET imaging and biodistribution studies in female Swiss Webster mice. Based on the biodistribution data, absorbed doses of 44 / 47 ScCl 3 in human adults were calculated for 18 organs and tissues using the IDAC-Dose software. Results: 44 Ti in 6 M HCl was loaded onto the organic resin generator with a yield of 99.97%. After loading and initial stabilization, 44 ScCl 3 was eluted with 0.05 M HCl in typical yields of 82.9 ± 5.3% (N = 16), which was normalized to the estimated generator capacity. Estimated generator capacity was computed based on elution time interval and the total amount of 44 Ti loaded on the generator. Run in forward and reverse directions, the 44 Sc/ 44 Ti ratio from a primary column was significantly improved from 1038 ± 440 to 3557 ± 680 (Bq/Bq) when a secondary, replaceable, ZR resin cartridge was employed at the flow outlet. In vivo imaging and ex vivo distribution studies of the reversible modular generator for 44 ScCl 3 , [ 44 Sc]-citrate and [ 44 Sc]-NODAGA show that free 44 Sc remained in the circulation significantly longer than the chelated 44 Sc. The dose estimation of 44 ScCl 3 reveals that the radiation burden is 0.146 mSv/MBq for a 70 kg adult male and 0.179 mSv/MBq for a 57 kg adult female. Liver, spleen and heart wall will receive the highest absorbed dose: 0.524, 0.502, and 0.303 mGy/MBq, respectively, for the adult male. Conclusions: A clinical-scale 44 Ti/ 44 Sc generator system with a modular design was developed to supply 44 ScCl 3 in 0.05 M HCl, which is suitable for further radiolabeling and in vivo use. Our data demonstrated that free 44 ScCl 3 remained in the circulation for extended periods, which resulted in approximately 10 times greater radiation burden than stably chelated 44 Sc. Stable 44 Sc/ 47 Sc-complexation will be more favorable for in vivo use and for clinical utility.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Production of Radiohalogens: Bromine and Astatine for Imaging and Therapy

Over the course of this two year grant, we have developed and optimized new methods for the production of clinical quality 76 Br, 77 Br, and 80m Br at the University of Wisconsin. This includes the synthesis of a novel isotopically enriched cobalt-selenium intermetallic compound, its fabrication into robust cyclotron targets, and the chemical isolation of the resulting bromine radionuclide. Compared with the previous state-of-the-art, these methods demonstrate a six-times larger 76 Br and three-times larger 77 Br production capacity for a 3-hour cyclotron irradiation. Additionally, the cyclotron targets are exceptionally robust to this process, allowing for their reuse for dozens of radiobromine productions.

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEA↗