A highly efficient deep red-emitting Mn4+-powered oxyfluoride nanophosphor developed for plant growth and optical thermometric applications.

This research mainly highlighted an intense deep red-emitting and Mn4+-powered oxyfluoride nanophosphor, Mg14Ge4.99O16F8:0.01Mn4+ (MGOF:Mn), which was synthesized via adopting a scalable synthesis route for commercial temperature sensing and artificial plant growth applications. The electron microscopic analysis confirmed the formation of nanosized particles without any defined shape or size distribution. The obtained nanophosphor exhibited sharp emission peaks at 659 nm and 631 nm under UV (317 nm) and blue excitation (417 nm) owing to Mn4+:2Eg → 4A2g and Mn4+:2T1g → 4A2g transitions, respectively. The emission spectrum is situated in the deep red region of the CIE color diagram where the red color purity approached 100% under both the excitations. The absorption efficiency and the internal and external quantum efficiencies of this red-emitting system were calculated to be 53%, ∼77%, and ∼41%, respectively, under blue excitation of 417 nm, which indicated its potential for indoor plant cultivation. A prototype red LED was fabricated by pasting the red-emitting MGOF:Mn4+ nanophosphor powder on a 410 nm blue LED chip. The resulting electroluminescence spectrum overlapped with those of the important organic pigments of normal plants. Importantly, the thermometric properties of the nanophosphor were evaluated in detail for FIR and lifetime-based thermometry applications. The examined nanophosphor showed an extreme absolute sensitivity of 0.00326 K-1 at 373 K with excellent reproducibility and temperature resolution. Because of the small particle size and high luminescence efficiency, the nanophosphor could be implemented in various nano-devices where non-contact optical thermometry is necessary for high performance.

Positron Emission Tomography Imaging of Cell Trafficking: A Method of Cell Radiolabeling.

Stem cell and chimeric antigen receptor (CAR) T-cell therapies are emerging as promising therapeutics for organ regeneration and as immunotherapy for various cancers. Despite significant progress having been made in these areas, there is still more to be learned to better understand the pharmacokinetics and pharmacodynamics of the administered therapeutic cells in the living system. For noninvasive, in vivo tracking of cells with positron emission tomography (PET), a novel [89Zr]Zr-p-isothiocyanatobenzyl-desferrioxamine ([89Zr]Zr-DBN)-mediated cell radiolabeling method has been developed utilizing 89Zr (t1/2 78.4 h). The present protocol describes a [89Zr]Zr-DBN-mediated, ready-to-use, radiolabeling synthon for direct radiolabeling of variety of cells, including mesenchymal stem cells, lineage-guided cardiopoietic stem cells, liver regenerating hepatocytes, white blood cells, melanoma cells, and dendritic cells. The developed methodology enables noninvasive PET imaging of cell trafficking for up to 7 days post-administration without affecting the nature or the function of the radiolabeled cells. Additionally, this protocol describes a stepwise method for the radiosynthesis of [89Zr]Zr-DBN, biocompatible formulation of [89Zr]Zr-DBN, preparation of cells for radiolabeling, and finally the radiolabeling of cells with [89Zr]Zr-DBN, including all the intricate details needed for the successful radiolabeling of cells.

Radiometals in Imaging and Therapy: Highlighting Two Decades of Research.

The present article highlights the important progress made in the last two decades in the fields of molecular imaging and radionuclide therapy. Advancements in radiometal-based positron emission tomography, single photon emission computerized tomography, and radionuclide therapy are illustrated in terms of their production routes and ease of radiolabeling. Applications in clinical diagnostic and radionuclide therapy are considered, including human studies under clinical trials; their current stages of clinical translations and findings are summarized. Because the metalloid astatine is used for imaging and radionuclide therapy, it is included in this review. In regard to radionuclide therapy, both beta-minus (ß-) and alpha (α)-emitting radionuclides are discussed by highlighting their production routes, targeted radiopharmaceuticals, and current clinical translation stage.

PET and SPECT Imaging of ALS: An Educational Review.

Amyotrophic lateral sclerosis (ALS) is a disease leading to progressive motor degeneration and ultimately death. It is a complex disease that can take a significantly long time to be diagnosed, as other similar pathological conditions must be ruled out for a definite diagnosis of ALS. Noninvasive imaging of ALS has shed light on disease pathology and altered biochemistry in the ALS brain. Other than magnetic resonance imaging (MRI), two types of functional imaging, positron emission tomography (PET) and single photon emission computed tomography (SPECT), have provided valuable data about what happens in the brain of ALS patients compared to healthy controls. PET imaging has revealed a specific pattern of brain metabolism through [18F]FDG, while other radiotracers have uncovered neuroinflammation, changes in neuronal density, and protein aggregation. SPECT imaging has shown a general decrease in regional cerebral blood flow (rCBF) in ALS patients. This educational review summarizes the current state of ALS imaging with various PET and SPECT radiopharmaceuticals to better understand the pathophysiology of ALS.

A Review of Theranostics: Perspectives on Emerging Approaches and Clinical Advancements.

Theranostics is the combination of two approaches-diagnostics and therapeutics-applied for decades in cancer imaging using radiopharmaceuticals or paired radiopharmaceuticals to image and selectively treat various cancers. The clinical use of theranostics has increased in recent years, with U.S. Food and Drug Administration (FDA) approval of lutetium 177 (177Lu) tetraazacyclododecane tetraacetic acid octreotate (DOTATATE) and 177Lu-prostate-specific membrane antigen vector-based radionuclide therapies. The field of theranostics has imminent potential for emerging clinical applications. This article reviews critical areas of active clinical advancement in theranostics, including forthcoming clinical trials advancing FDA-approved and emerging radiopharmaceuticals, approaches to dosimetry calculations, imaging of different radionuclide therapies, expanded indications for currently used theranostic agents to treat a broader array of cancers, and emerging ideas in the field. Keywords: Molecular Imaging, Molecular Imaging-Cancer, Molecular Imaging-Clinical Translation, Molecular Imaging-Target Development, PET/CT, SPECT/CT, Radionuclide Therapy, Dosimetry, Oncology, Radiobiology © RSNA, 2023.

Isotopic composition of serum zinc and copper in healthy children and children with autism spectrum disorder in North America.

To better understand zinc and copper regulation and their involvement in various biochemical pathways as it relates to autism spectrum disorder (ASD), isotopic composition of serum zinc and copper were evaluated in both healthy children and children with ASD in North America. No significant difference in isotopic composition of serum zinc or copper with respect to healthy controls and ASD children were identified. However, the isotopic composition of serum copper in boys was found to be enriched in 65Cu in comparison to previously published healthy adult copper isotopic composition. Furthermore, in both boys and girls, the average isotopic composition of serum zinc is heavier than previously published healthy adult isotopic zinc composition. There was also a negative association between total zinc concentrations in serum and the zinc isotopic composition of serum in boys. Finally, children with heavier isotopic composition of copper also showed a high degree of variability in their zinc isotopic composition. While numerous studies have measured the isotopic composition of serum zinc and copper in adults, this is one of the first studies which measured the isotopic composition of serum copper and zinc in children, specifically those diagnosed with ASD. The results of this study showed that age and gender specific normal ranges of isotopic composition must be established to effectively use isotopic composition analysis in studying various diseases including ASD.

The role of selenoproteins in neurodevelopment and neurological function: Implications in autism spectrum disorder.

Selenium and selenoproteins play a role in many biological functions, particularly in brain development and function. This review outlines the role of each class of selenoprotein in human brain function. Most selenoproteins play a large antioxidant role within the brain. Autism spectrum disorder (ASD) has been shown to correlate with increased oxidative stress, and the presumption of selenoproteins as key players in ASD etiology are discussed. Further, current literature surrounding selenium in ASD and selenium supplementation studies are reviewed. Finally, perspectives are given for future directions of selenoprotein research in ASD.

Evaluation of different 89Zr-labeled synthons for direct labeling and tracking of white blood cells and stem cells in healthy athymic mice.

Cell based therapies are evolving as an effective new approach to treat various diseases. To understand the safety, efficacy, and mechanism of action of cell-based therapies, it is imperative to follow their biodistribution noninvasively. Positron-emission-tomography (PET)-based non-invasive imaging of cell trafficking offers such a potential. Herein, we evaluated and compared three different ready-to-use direct cell radiolabeling synthons, [89Zr]Zr-DFO-Bn-NCS, [89Zr]Zr-Hy3ADA5-NCS, and [89Zr]Zr-Hy3ADA5-SA for PET imaging-based trafficking of white blood cells (WBCs) and stem cells (SCs) up to 7 days in athymic nude mice. We compared the degree of 89Zr complexation and percentage of cell radiolabeling efficiencies with each. All three synthons, [89Zr]Zr-DFO-Bn-NCS, [89Zr]Zr-Hy3ADA5-NCS, and [89Zr]Zr-Hy3ADA5-SA, were successfully prepared, and used for radiolabeling of WBCs and SCs. The highest cell radiolabeling yield was found for [89Zr]Zr-DFO-Bn-NCS, followed by [89Zr]Zr-Hy3ADA5-NCS, and [89Zr]Zr-Hy3ADA5-SA. In terms of biodistribution, WBCs radiolabeled with [89Zr]Zr-DFO-Bn-NCS or [89Zr]Zr-Hy3ADA5-NCS, were primarily accumulated in liver and spleen, whereas SCs radiolabeled with [89Zr]Zr-DFO-Bn-NCS or [89Zr]Zr-Hy3ADA5-NCS were found in lung, liver and spleen. A high bone uptake was observed for both WBCs and SCs radiolabeled with [89Zr]Zr-Hy3ADA5-SA, suggesting in-vivo instability of [89Zr]Zr-Hy3ADA5-SA synthon. This study offers an appropriate selection of ready-to-use radiolabeling synthons for noninvasive trafficking of WBCs, SCs and other cell-based therapies.

Design, Synthesis, and Preliminary Evaluation of [68Ga]Ga-NOTA-Insulin as a PET Probe in an Alzheimer's Disease Mouse Model.

Aberrant insulin signaling has been considered one of the risk factors for the development of Alzheimer's disease (AD) and has drawn considerable attention from the research community to further study its role in AD pathophysiology. Herein, we describe the development of an insulin-based novel positron emission tomography (PET) probe, [68Ga]Ga-NOTA-insulin, to noninvasively study the role of insulin in AD. The developed PET probe [68Ga]Ga-NOTA-insulin showed a significantly higher uptake (0.396 ± 0.055 SUV) in the AD mouse brain compared to the normal (0.140 ± 0.027 SUV) mouse brain at 5 min post injection and also showed a similar trend at 10, 15, and 20 min post injection. In addition, [68Ga]Ga-NOTA-insulin was found to have a differential uptake in various brain regions at 30 min post injection. Among the brain regions, the cortex, thalamus, brain stem, and cerebellum showed a significantly higher standard uptake value (SUV) of [68Ga]Ga-NOTA-insulin in AD mice as compared to normal mice. The inhibition of the insulin receptor (IR) with an insulin receptor antagonist peptide (S961) in normal mice showed a similar brain uptake profile of [68Ga]Ga-NOTA-insulin as it was observed in the AD case, suggesting nonfunctional IR in AD and the presence of an alternative insulin uptake route in the absence of a functional IR. The Gjedde-Patlak graphical analysis was also performed to predict the input rate of [68Ga]Ga-NOTA-insulin into the brain using MicroPET imaging data and supported the in vivo results. The [68Ga]Ga-NOTA-insulin PET probe was successfully synthesized and evaluated in a mouse model of AD in comparison with [18F]AV1451 and [11C]PIB to noninvasively study the role of insulin in AD pathophysiology.

Dynamic Imaging of Chimeric Antigen Receptor T Cells with [18F]Tetrafluoroborate Positron Emission Tomography/Computed Tomography.

T cells genetically engineered to express chimeric antigen receptors (CAR) have shown unprecedented results in pivotal clinical trials for patients with B cell malignancies or multiple myeloma (MM). However, numerous obstacles limit the efficacy and prohibit the widespread use of CAR T cell therapies due to poor trafficking and infiltration into tumor sites as well as lack of persistence in vivo. Moreover, life-threatening toxicities, such as cytokine release syndrome or neurotoxicity, are major concerns. Efficient and sensitive imaging and tracking of CAR T cells enables the evaluation of T cell trafficking, expansion, and in vivo characterization and allows the development of strategies to overcome the current limitations of CAR T cell therapy. This paper describes the methodology for incorporating the sodium iodide symporter (NIS) in CAR T cells and for CAR T cell imaging using [18F]tetrafluoroborate-positron emission tomography ([18F]TFB-PET) in preclinical models. The methods described in this protocol can be applied to other CAR constructs and target genes in addition to the ones used for this study.

A new solid target design for the production of 89Zr and radiosynthesis of high molar activity [89Zr]Zr-DBN.

Due to the advent of various biologics like antibodies, proteins, cells, viruses, and extracellular vesicles as biomarkers for disease diagnosis, progression, and as therapeutics, there exists a need to have a simple and ready to use radiolabeling synthon to enable noninvasive imaging trafficking studies. Previously, we reported [89Zr]zirconium-p-isothiocyanatobenzyl-desferrioxamine ([89Zr]Zr-DBN) as a synthon for the radiolabeling of biologics to allow PET imaging of cell trafficking. In this study, we focused on improving the molar activity (Am) of [89Zr]Zr-DBN, by enhancing 89Zr production on a low-energy cyclotron and developing a new reverse phase HPLC method to purify [89Zr]Zr-DBN. To enhance 89Zr production, a new solid target was designed, and production yield was optimized by varying, thickness of yttrium foil, beam current, irradiation duration and proton beam energy. After optimization, 4.78±0.33 GBq (129.3±8.9 mCi) of 89Zr was produced at 40 µA for 180 min (3 h) proton irradiation decay corrected to the end of bombardment with a saturation yield of 4.56±0.31 MBq/µA. Additionally, after reverse phase HPLC purification the molar activity of [89Zr]Zr-DBN was found to be in 165-316 GBq/µmol range. The high molar activity of [89Zr]Zr-DBN also allowed radiolabeling of low concentration of proteins in relatively higher yield. The stability of [89Zr]Zr-DBN was measured over time with and without the presence of ascorbic acid. The newly designed solid target assembly and HPLC method of [89Zr]Zr-DBN purification can be adopted in the routine production of 89Zr and [89Zr]Zr-DBN, respectively.

Corrigendum: Evaluation of Zn, Cu, and Se Levels in the North American Autism Spectrum Disorder Population.

[This corrects the article DOI: 10.3389/fnmol.2021.665686.].

Unusual Increased Blood Pool Activity on 68Ga-DOTATATE PET/CT in a Patient With Metastatic Neuroendocrine Disease.

ABSTRACT: 68Ga-DOTATATE is a well-established, positron-emitting, somatostatin receptor-binding radiopharmaceutical. We present an unusual case of transiently increased blood pool uptake of 68Ga-DOTATATE in a patient with well-differentiated stage IV neuroendocrine tumor, with Ki-67 <2% (WHO grade 1) maintained on lanreotide. During serial 68Ga-DOTATATE PET/CT examinations, increased blood pool accumulation of presumably unbound 68Ga was demonstrated, which could impact the Kenning score and lead to a false treatment response assessment.

Development of a Clinically Relevant Reporter for Chimeric Antigen Receptor T-cell Expansion, Trafficking, and Toxicity.

Although chimeric antigen receptor T (CART)-cell therapy has been successful in treating certain hematologic malignancies, wider adoption of CART-cell therapy is limited because of minimal activity in solid tumors and development of life-threatening toxicities, including cytokine release syndrome (CRS). There is a lack of a robust, clinically relevant imaging platform to monitor in vivo expansion and trafficking to tumor sites. To address this, we utilized the sodium iodide symporter (NIS) as a platform to image and track CART cells. We engineered CD19-directed and B-cell maturation antigen (BCMA)-directed CART cells to express NIS (NIS+CART19 and NIS+BCMA-CART, respectively) and tested the sensitivity of 18F-TFB-PET to detect trafficking and expansion in systemic and localized tumor models and in a CART-cell toxicity model. NIS+CART19 and NIS+BCMA-CART cells were generated through dual transduction with two vectors and demonstrated exclusive 125I uptake in vitro. 18F-TFB-PET detected NIS+CART cells in vivo to a sensitivity level of 40,000 cells. 18F-TFB-PET confirmed NIS+BCMA-CART-cell trafficking to the tumor sites in localized and systemic tumor models. In a xenograft model for CART-cell toxicity, 18F-TFB-PET revealed significant systemic uptake, correlating with CART-cell in vivo expansion, cytokine production, and development of CRS-associated clinical symptoms. NIS provides a sensitive, clinically applicable platform for CART-cell imaging with PET scan. 18F-TFB-PET detected CART-cell trafficking to tumor sites and in vivo expansion, correlating with the development of clinical and laboratory markers of CRS. These studies demonstrate a noninvasive, clinically relevant method to assess CART-cell functions in vivo.

Non-invasive immunoPET imaging of PD-L1 using anti-PD-L1-B11 in breast cancer and melanoma tumor model.

INTRODUCTION: Immunotherapy targeting PD-1/PD-L1 immune checkpoint inhibition (ICI) is efficacious in various solid and hematologic malignancies. However, the response rate to PD-1/PD-L1 therapy is only 15-35%. To obtain optimal clinical response to ICI therapies, a reliable assessment of tumor PD-L1 expression is needed to select appropriate patients, and a non-invasive imaging-based assessment of PD-L1 expression is critically needed. Although radiolabeled PET probes based on PD-L1 targeted therapeutic antibodies (e.g. atezolizumab) have shown encouraging results, there is concern that residual therapeutic antibody may compete for binding with the radiotracer thereby compromising imaging studies that follow treatment. METHODS AND RESULTS: In this study, we used novel anti-PD-L1-B11 clone antibody known to bind to a different epitope of PD-L1 than the therapeutic antibodies to avoid potential saturation effects. The anti-PD-L1-B11 clone was radiolabeled with zirconium-89 and evaluated to detect PD-L1 expression in various in vitro and in vivo cancer model systems in comparison with [89Zr]Zr-DFO-NCS-atezolizumab. In vitro binding parameters of anti-PD-L1-B11 were like those of atezolizumab. [89Zr]Zr-DFO-NCS-anti-PD-L1-B11 clone showed favorable properties to [89Zr]Zr-DFO-NCS-atezolizumab in an in vivo breast cancer tumor model system with higher uptake in PD-L1 expressing tumors. CONCLUSION: Our data demonstrates that [89Zr]Zr-DFO-NCS-anti-PD-L1-B11 exhibits excellent imaging properties for the assessment PD-L1 expression. The independent binding site of anti-PD-L1-B11 relative to therapeutic anti-PD-L1 antibodies may be advantageous for anti-PD-L1 therapy monitoring.

Evaluation of Zn, Cu, and Se Levels in the North American Autism Spectrum Disorder Population.

Metal ion dyshomeostasis and disparate levels of biometals like zinc (Zn), copper (Cu), and selenium (Se) have been implicated as a potential causative factor for Autism Spectrum Disorder (ASD). In this study, we have enrolled 129 children (aged 2-4 years) in North America, of which 64 children had a diagnosis of ASD and 65 were controls. Hair, nail, and blood samples were collected and quantitatively analyzed for Zn, Cu and Se using inductively coupled plasma mass spectrometry (ICP-MS). Of the analyzed biometals, serum Se (116.83 ± 14.84 mcg/mL) was found to be significantly lower in male ASD cases compared to male healthy controls (128.21 ± 9.11 mcg/mL; p < 0.005). A similar trend was found for nail Se levels in ASD (1.01 ± 0.15 mcg/mL) versus that of controls (1.11 ± 0.17 mcg/mL) with a p-value of 0.0132 using a stratified Wilcoxon rank sum testing. The level of Se in ASD cohort was co-analyzed for psychometric correlation and found a negative correlation between total ADOS score and serum Se levels. However, we did not observe any significant difference in Zn, Cu, and Zn/Cu ratio in ASD cases versus controls in this cohort of North American children. Further studies are recommended to better understand the biology of the relationship between Se and ASD status.

Cyclotron Production of PET Radiometals in Liquid Targets: Aspects and Prospects.

The present review describes the methodological aspects and prospects of the production of Positron Emission Tomography (PET) radiometals in a liquid target using low-medium energy medical cyclotrons. The main objective of this review is to delineate and discuss the critical factors involved in the liquid target production of radiometals, including type of salt solution, solution composition, beam energy, beam current, the effect of irradiation duration (length of irradiation) and challenges posed by in-target chemistry in relation with irradiation parameters. We also summarize the optimal parameters for the production of various radiometals in liquid targets. Additionally, we discuss the future prospects of PET radiometals production in the liquid targets for academic research and clinical applications. Significant emphasis has been given to the production of 68Ga using liquid targets due to the growing demand for 68Ga labeled PSMA vectors, [68Ga]- Ga-DOTATATE, [68Ga]Ga-DOTANOC and some upcoming 68Ga labeled radiopharmaceuticals. Other PET radiometals included in the discussion are 86Y, 63Zn and 89Zr.

Abnormal Levels of Metal Micronutrients and Autism Spectrum Disorder: A Perspective Review.

The aim of the present review is to summarize the prevalence of abnormal levels of various metal micronutrients including copper (Cu), iron (Fe), magnesium (Mg), zinc (Zn), and selenium (Se) in Autism Spectrum Disorder (ASD) using hair, nail and serum samples. A correlation of selected abnormal metal ions with known neurodevelopmental processes using Gene Ontology (GO) term was also conducted. Data included in this review are derived from ASD clinical studies performed globally. Metal ion disparity data is also analyzed and discussed based on gender (Male/Female) to establish any gender dependent correlation. Finally, a rational perspective and possible path to better understand the role of metal micronutrients in ASD is suggested.