Combining Nuclear Medicine With Other Modalities: Future Prospect for Multimodality Imaging.

This meeting report summarizes a consultants meeting that was held at International Atomic Energy Agency Headquarters, Vienna, in July 2022 to provide an update on the development of multimodality imaging by combining nuclear medicine imaging agents with other nonradioactive molecular probes and/or biomedical imaging techniques.

Recent advances and impending challenges for the radiopharmaceutical sciences in oncology.

This paper is the first of a Series on theranostics that summarises the current landscape of the radiopharmaceutical sciences as they pertain to oncology. In this Series paper, we describe exciting developments in radiochemistry and the production of radionuclides, the development and translation of theranostics, and the application of artificial intelligence to our field. These developments are catalysing growth in the use of radiopharmaceuticals to the benefit of patients worldwide. We also highlight some of the key issues to be addressed in the coming years to realise the full potential of radiopharmaceuticals to treat cancer.

Production and regulatory issues for theranostics.

Theranostics has become a major area of innovation and progress in cancer care over the last decade. In view of the introduction of approved therapeutics in neuroendocrine tumours and prostate cancer in the last 10 years, the ability to provide access to these treatments has emerged as a key factor in ensuring global benefits from this cancer therapy approach. In this Series paper we explore the issues that affect access to and availability of theranostic radiopharmaceuticals, including supply and regulatory issues that might affect the availability of theranostic treatments for patients with cancer.

Trends in nuclear medicine and the radiopharmaceutical sciences in oncology: workforce challenges and training in the age of theranostics.

Although the promise of radionuclides for the diagnosis and treatment of disease was recognised soon after the discovery of radioactivity in the late 19th century, the systematic use of radionuclides in medicine only gradually increased over the subsequent hundred years. The past two decades, however, has seen a remarkable surge in the clinical application of diagnostic and therapeutic radiopharmaceuticals, particularly in oncology. This development is an exciting time for the use of theranostics in oncology, but the rapid growth of this area of nuclear medicine has created challenges as well. In particular, the infrastructure for the manufacturing and distribution of radiopharmaceuticals remains in development, and regulatory bodies are still optimising guidelines for this new class of drug. One issue of paramount importance for achieving equitable access to theranostics is building a sufficiently trained workforce in high-income, middle-income, and low-income countries. Here, we discuss the key challenges and opportunities that face the field as it seeks to build its workforce for the 21st century.

Position paper to facilitate patient access to radiopharmaceuticals: considerations for a suitable pharmaceutical regulatory framework.

BACKGROUND: Nuclear medicine has made enormous progress in the past decades. However, there are still significant inequalities in patient access among different countries, which could be mitigated by improving access to and availability of radiopharmaceuticals. MAIN BODY: This paper summarises major considerations for a suitable pharmaceutical regulatory framework to facilitate patient access to radiopharmaceuticals. These include the distinct characteristics of radiopharmaceuticals which require dedicated regulations, considering the impact of the variable complexity of radiopharmaceutical preparation, personnel requirements, manufacturing practices and quality assurance, regulatory authority interfaces, communication and training, as well as marketing authorisation procedures to ensure availability of radiopharmaceuticals. Finally, domestic and regional supply to ensure patient access via alternative regulatory pathways, including in-house production of radiopharmaceuticals, is described, and an outlook on regulatory challenges faced by new developments, such as the use of alpha emitters, is provided. CONCLUSIONS: All these considerations are an outcome of a dedicated Technical Meeting organised by the IAEA in 2023 and represent the views and opinions of experts in the field, not those of any regulatory authorities.

Proceedings of international symposium of trends in radiopharmaceuticals 2023 (ISTR-2023).

The International Atomic Energy Agency (IAEA) held the 3rd International Symposium on Trends in Radiopharmaceuticals, (ISTR-2023) at IAEA Headquarters in Vienna, Austria, during the week of 16-21 April 2023. This procedural paper summarizes highlights from symposium presentations, posters, panel discussions and satellite meetings, and provides additional resources that may be useful to researchers working with diagnostic and therapeutic radiopharmaceuticals in the academic, government and industry setting amongst IAEA Member States and beyond. More than 550 participants in person from 88 Member States attended the ISTR-2023. Over 360 abstracts were presented from all over the world by a diverse group of global scientists working with radiopharmaceuticals. Given this group of international radiochemists is unique to ISTR (IAEA funding enabled many to attend), there was an invaluable wealth of knowledge on the global state of the radiopharmaceutical sciences present at the meeting. The intent of this Proceedings paper is to share this snapshot from our international colleagues with the broader radiopharmaceutical sciences community by highlighting presentations from the conference on the following topics: Isotope Production and Radiochemistry, Industrial Insights, Regional Trends, Training and Education, Women in the Radiopharmaceutical Sciences, and Future Perspectives and New Initiatives. The authors of this paper are employees of IAEA, members of the ISTR-2023 Organizing Committee and/or members of the EJNMMI Radiopharmacy and Chemistry Editorial Board who attended ISTR-2023. Overall, ISTR-2023 fostered the successful exchange of scientific ideas around every aspect of the radiopharmaceutical sciences. It was well attended by a diverse mix of radiopharmaceutical scientists from all over the world, and the oral and poster presentations provided a valuable update on the current state-of-the-art of the field amongst IAEA Member States. Presentations as well as networking amongst the attendees resulted in extensive knowledge transfer amongst the various stakeholders representing 88 IAEA Member States. This was considered particularly valuable for attendees from Member States where nuclear medicine and the radiopharmaceutical sciences are still relatively new. Since the goal is for the symposium series to be held every four years; the next one is anticipated to take place in 2027.

Zirconium Coordination Chemistry and Its Role in Optimizing Hydroxymate Chelation: Insights from Molecular Dynamics.

In the past decade, there has been a growth in using Zirconium-89 (89Zr) as a radionuclide in nuclear medicine for cancer diagnostic imaging and drug discovery processes. Although one of the most popular chelators for 89Zr, desferrioxamine (DFO) is typically presented as a hexadentate ligand, our work suggests a different scenario. The coordination structure of the Zr4+-DFO complex has primarily been informed by DFT-based calculations, which typically ignore temperature and therefore entropic and dynamic solvent effects. In this work, free energy calculations using molecular dynamics simulations, where the conformational fluctuations of both the ligand and the solvent are explicitly included, are used to compare the binding of Zr4+ cations with two different chelators, DFO and 4HMS, the latter of which is an octadentate ligand that has been recently proposed as a better chelator due to the presence of four hydroxymate groups. We find that thermally induced disorder leads to an open hexadentate chelate structure of the Zr4+-DFO complex, leaving the Zr4+ metal exposed to the solvent. A stable coordination of Zr4+ with 4HMS, however, is formed by involving both hydroxamate groups and water molecules in a more closely packed structure.

The Development and Validation of Radiopharmaceuticals Targeting Bacterial Infection.

The International Atomic Energy Agency organized a technical meeting at its headquarters in Vienna, Austria, in 2022 that included 17 experts representing 12 countries, whose research spanned the development and use of radiolabeled agents for imaging infection. The meeting focused largely on bacterial pathogens. The group discussed and evaluated the advantages and disadvantages of several radiopharmaceuticals, as well as the science driving various imaging approaches. The main objective was to understand why few infection-targeted radiotracers are used in clinical practice despite the urgent need to better characterize bacterial infections. This article summarizes the resulting consensus, at least among the included scientists and countries, on the current status of radiopharmaceutical development for infection imaging. Also included are opinions and recommendations regarding current research standards in this area. This and future International Atomic Energy Agency-sponsored collaborations will advance the goal of providing the medical community with innovative, practical tools for the specific image-based diagnosis of infection.

Marshalling the Potential of Auger Electron Radiopharmaceutical Therapy.

Auger electron (AE) radiopharmaceutical therapy (RPT) may have the same therapeutic efficacy as α-particles for oncologic small disease, with lower risks of normal-tissue toxicity. The seeds of using AE emitters for RPT were planted several decades ago. Much knowledge has been gathered about the potency of the biologic effects caused by the intense shower of these low-energy AEs. Given their short range, AEs deposit much of their energy in the immediate vicinity of their site of decay. However, the promise of AE RPT has not yet been realized, with few agents evaluated in clinical trials and none becoming part of routine treatment so far. Instigated by the 2022 "Technical Meeting on Auger Electron Emitters for Radiopharmaceutical Developments" at the International Atomic Energy Agency, this review presents the current status of AE RPT based on the discussions by experts in the field. A scoring system was applied to illustrate hurdles in the development of AE RPT, and we present a selected list of well-studied and emerging AE-emitting radionuclides. Based on the number of AEs and other emissions, physical half-life, radionuclide production, radiochemical approaches, dosimetry, and vector availability, recommendations are put forward to enhance and impact future efforts in AE RPT research.

Practical considerations for navigating the regulatory landscape of non-clinical studies for clinical translation of radiopharmaceuticals.

BACKGROUND: The development of radiopharmaceuticals requires extensive evaluation before they can be applied in a diagnostic or therapeutic setting in Nuclear Medicine. Chemical, radiochemical, and pharmaceutical parameters must be established and verified to ensure the quality of these novel products. MAIN BODY: To provide supportive evidence for the expected human in vivo behaviour, particularly related to safety and efficacy, additional tests, often referred to as "non-clinical" or "preclinical" are mandatory. This document is an outcome of a Technical Meeting of the International Atomic Energy Agency. It summarises the considerations necessary for non-clinical studies to accommodate the regulatory requirements for clinical translation of radiopharmaceuticals. These considerations include non-clinical pharmacology, radiation exposure and effects, toxicological studies, pharmacokinetic modelling, and imaging studies. Additionally, standardisation of different specific clinical applications is discussed. CONCLUSION: This document is intended as a guide for radiopharmaceutical scientists, Nuclear Medicine specialists, and regulatory professionals to bring innovative diagnostic and therapeutic radiopharmaceuticals into the clinical evaluation process in a safe and effective way.

Current status on cyclotron facilities and related infrastructure supporting PET applications in Latin America and the Caribbean.

This review presents the results of a survey conducted by the International Atomic Energy Agency on cyclotrons and related infrastructure used for radionuclide and radiopharmaceutical production which are supporting PET imaging applications in Latin America and the Caribbean region.

Architectured Therapeutic and Diagnostic Nanoplatforms for Combating SARS-CoV-2: Role of Inorganic, Organic, and Radioactive Materials.

Although extensive research is being done to combat SARS-CoV-2, we are yet far away from a robust conclusion or strategy. With an increased amount of vaccine research, nanotechnology has found its way into vaccine technology. Researchers have explored the use of various nanostructures for delivering the vaccines for enhanced efficacy. Apart from acting as delivery platforms, multiple studies have shown the application of inorganic nanoparticles in suppressing the growth as well as transmission of the virus. The present review gives a detailed description of various inorganic nanomaterials which are being explored for combating SARS-CoV-2 along with their role in suppressing the transmission of the virus either through air or by contact with inanimate surfaces. The review further discusses the use of nanoparticles for development of an antiviral coating that may decrease adhesion of SARS-CoV-2. A separate section has been included describing the role of nanostructures in biosensing and diagnosis of SARS-CoV-2. The role of nanotechnology in providing an alternative therapeutic platform along with the role of radionuclides in SARS-CoV-2 has been described briefly. Based on ongoing research and commercialization of this nanoplatform for a viral disease, the nanomaterials show the potential in therapy, biosensing, and diagnosis of SARS-CoV-2.

IAEA Activities on 67Cu, 186Re, 47Sc Theranostic Radionuclides and Radiopharmaceuticals.

Despite interesting properties, the use of 67Cu, 186Re and 47Sc theranostic radionuclides in preclinical studies and clinical trials is curtailed by their limited availability due to a lack of widely established production methods. An IAEA Coordinated Research Project (CRP) was initiated to identify important technical issues related to the production and quality control of these emerging radionuclides and related radiopharmaceuticals, based on the request from IAEA Member States. The international team worked on targetry, separation, quality control and radiopharmaceutical aspects of the radionuclides obtained from research reactors and cyclotrons leading to preparation of a standard recommendations for all Member States. The CRP was initiated in 2016 with fourteen participants from thirteen Member States from four continents. Extraordinary results on the production, quality control and preclinical evaluation of selected radionuclides were reported in this project that was finalized in 2020. The outcomes, outputs and results of this project achieved by participating Member States are described in this minireview.

Standardization of type 1 and type 2 diabetic nephropathy models in rats: Assessment and characterization of metabolic features and renal injury.

BACKGROUND: Diabetes mellitus and its complications, such as nephropathy, represent a global burden. Recent research focuses on developing drugs that specifically target the pathogenesis of diabetic nephropathy rather than merely treating hyperglycemia. Rodent models of animal disease are integral in drug discovery and represent an obligatory regulatory requirement. AIM: The aim of this study was to develop and standardize rat models of type 1 and type 2 diabetic nephropathy, resembling characteristics of human clinical condition. MATERIALS AND METHODS: Rats were administered streptozotocin (STZ) 50 mg/kg intraperitoneally (i.p.), and STZ 50 mg/kg i.p. + nicotinamide (NA) 110 mg/kg i.p., for induction of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), respectively. Metabolic parameters (body weight, feed and water intake, blood glucose, serum insulin, oral glucose tolerance test, intraperitoneal insulin tolerance test, and indices of insulin sensitivity) were evaluated to characterize the symptoms of T1DM and T2DM. Renal damage was confirmed by the estimation of renal function biomarkers, kidney antioxidant status, kidney hypertrophy index, and histopathology. RESULTS: STZ and STZ + NA administration increased blood glucose levels significantly. Metabolic parameters indicated that administration of STZ resulted in clinical features of human T1DM, whereas STZ + NA rats resembled human T2DM. STZ- and STZ + NA-treated rats developed diabetic nephropathy in 4 weeks, indicated by altered levels of renal function markers, increased kidney hypertrophy index, increased renal oxidative stress, and altered tissue architecture. The study proposes reproducible and cost-effective rat models for both T1DM- and T2DM-induced diabetic nephropathy characterized by stable metabolic features and typical renal lesions.

Radionuclide Imaging for Neuroscience: Current Opinion and Future Directions.

This meeting report summarizes a Consultants Meeting that was held at International Atomic Energy Agency headquarters in Vienna to provide an update on radionuclide imaging for neuroscience applications.

Studies on batch formulation of a freeze dried kit for the preparation of 99mTc-HYNIC-TATE for imaging neuroendocrine tumors.

AIM: To formulate freeze dried cold kits for preparation of 99mTc-HYNIC-TATE suitable for use at hospital radiopharmacy and establish clinical utility of 99mTc-HYNIC-TATE prepared using kits for detection of neuroendocrine tumors (NETs). METHODS: Standardization of reagent concentrations for formulation of freeze dried kits of HYNIC-TATE was carried out. Consistency in formulation was tested by six batch preparation. Quality control tests were carried out to establish compliance of specifications of purity and safety criteria for both kits and 99mTc-HYNIC-TATE formulated using kits. Clinical utility of 99mTc-HYNIC-TATE prepared using kits was demonstrated in patients with histopathologically confirmed well-differentiated NETs. RESULTS: Pharmaceutical grade HYNIC-TATE kits compliant with all the quality control criteria were formulated and successfully radiolabeled with 99mTc. Radiopharmaceutical was successfully utilized for detection of NETs in patients and comparison with uptake of 99mTc-HYNIC-TOC and 177Lu-DOTA-TATE was made. CONCLUSION: The formulated kits are robust and provide consistently high radiolabeling yields (> 95%) with 99mTc in short time periods requiring no additional purification. Initial clinical trials demonstrate the utility of 99mTc-HYNIC-TATE using formulated kits.

68Ga-NOTA-ubiquicidin fragment for PET imaging of infection: From bench to bedside.

This study explores the possibility of formulation of a cold kit for fast and easy preparation of a PET radiopharmaceutical, 68Ga-NOTA-UBI (29-41) for clinical translation. In this study, Circular dichroism (CD) spectroscopy to study conformation of NOTA-UBI (29-41) and its comparison with conformation of UBI (29-41) was done. Pharmaceutical grade cold kits of NOTA-UBI (29-41) were formulated for radiolabeling with 68Ga and necessary quality control tests were carried out. 68Ga-NOTA-UBI (29-41) could be prepared in >90% radiochemical yield and radiochemical purity using cold kits of NOTA-UBI (29-41). In vitro and in vivo evaluation of 68Ga-NOTA-UBI (29-41) was done to demonstrate specificity of the agent for imaging infection. Kits were utilized for preparation of patient dose of 68Ga-NOTA-UBI (29-41). Simple instant thin layer chromatography (ITLC) method for estimating radiolabeling yield of 68Ga-NOTA-UBI (29-41) at hospital radiopharmacy was demonstrated. Clinical evaluation was done in patients with suspected infection. 148-185 MBq of 68Ga-NOTA-UBI (29-41) was injected intravenously in three patients. 68Ga-NOTA-UBI (29-41) uptake could clearly delineate infection foci from non target normal tissues. This is the first report on formulation of a cold kit of NOTA-UBI (29-41) for preparation of 68Ga labeled NOTA-UBI(29-41) at hospital radiopharmacy for infection imaging. Initial clinical evaluation reveal it to be a prospective agent for imaging infection.

177 Lu-DOTMP induces G2/M cell cycle arrest and apoptosis in MG63 cell line.

Bone pain is the major manifestation of skeletal metastases. Although various treatment modalities are available for bone pain palliation, use of radiolabeled phosphonates is documented to be more effective. Among radionuclides available for this purpose, lutetium-177 is gaining popularity due to its moderate beta energy, theranostic capability, favorable half-life and convenient production logistics. 177 Lu-DOTMP has shown considerable promise as a metastatic bone pain palliating agent in preliminary evaluations and recent clinical studies. Therefore, an attempt was made to elucidate the possible mechanism of in vitro cell death induced by 177 Lu-DOTMP in MG63 cells. 177 Lu-DOTMP binding studies were carried out in mineralized bone of MG63 cells and around 50% binding was observed. Skeletons of Wistar rats showed 1.78 ± 0.5% IA/g at a 3 h time period which was almost constant up to 7 days. MG63 cells were incubated with 3.7 and 37 MBq of 177 Lu-DOTMP for 48 h prior to perform assays. An increase in the magnitude of cell toxicity and apoptotic DNA fragmentation was observed. Enhancement of G2/M phase cell cycle arrest and apoptosis were documented which were dose-dependent. Thus, 177 Lu-DOTMP induced apoptotic cell death in MG63 cells, which might be one of the primary causes of pain relief in osseous metastases.

Gallium-68 labeled Ubiquicidin derived octapeptide as a potential infection imaging agent.

INTRODUCTION: Gallium-68 based infection imaging agents are in demand to detect infection foci with high spatial resolution and sensitivity. In this study, Ubiquicidin derived octapeptide, UBI (31-38) conjugated with macrocyclic chelator NOTA was radiolabeled with 68Ga to develop infection imaging agent. METHODS: Circular dichroism (CD) spectroscopy was performed to study conformational changes in UBI (31-38) and its NOTA conjugate in a "membrane like environment". Radiolabeling of NOTA-UBI (31-38) with 68Ga was optimized and quality control analysis was done by chromatography techniques. In vitro evaluation of 68Ga-NOTA-UBI (31-38) in S. aureus and preliminary biological evaluation in animal model of infection was studied. Initial clinical evaluation in three patients with suspected infection was carried out. RESULTS: 68Ga-NOTA-UBI (31-38) was prepared in high radiochemical yields and high radiochemical purity. In vitro evaluation of 68Ga-NOTA-UBI (31-38) complex in S. aureus confirmed specificity of the agent for bacteria. Biodistribution studies with 68Ga-NOTA-UBI (31-38) revealed specific uptake of the complex in infected muscle compared to inflamed muscle with T/NT ratio of 3.24 ±â€¯0.7 at 1 h post-injection. Initial clinical evaluation in two patients with histopathologically confirmed infective foci conducted after intravenous injection of 130-185 MBq of 68Ga-NOTA-UBI (31-38) and imaging at 45-60 min post-injection revealed specific uptake at the sites of infection and clearance from vital organs. No uptake of tracer was observed in suspected infection foci in one patient, which was proven to be aseptic and served as negative control. CONCLUSION: This is the first report on 68Ga labeled NOTA-UBI (31-38) fragment for prospective infection imaging.