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At least 19 records

Overcoming Barriers to Radiopharmaceutical Therapy (RPT): An Overview From the NRG-NCI Working Group on Dosimetry of Radiopharmaceutical Therapy

Radiopharmaceutical therapy (RPT) continues to demonstrate tremendous potential in improving the therapeutic gains in radiation therapy by specifically delivering radiation to tumors that can be well assessed in terms of dosimetry and imaging. Dosimetry in external beam radiation therapy is standard practice. This is not the case, however, in RPT. This NRG (acronym formed from the first letter of the 3 original groups: National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group)-National Cancer Institute Working Group review describes some of the challenges to improving RPT. The main priorities for advancing the field include (1) developing and adopting best practice guidelines for incorporating patient-specific dosimetry for RPT that can be used at both large clinics with substantial resources and more modest clinics that have limited resources, (2) establishing and improving strategies for introducing new radiopharmaceuticals for clinical investigation, (3) developing approaches to address the radiophobia that is associated with the administration of radioactivity for cancer therapy, and (4) solving the financial and logistical issues of expertise and training in the developing field of RPT.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Global Issues of Radiopharmaceutical Access and Availability: a Nuclear Medicine Global Initiative Project

The Nuclear Medicine Global Initiative (NMGI) was formed in 2012 by 13 international organizations to promote human health by advancing the field of nuclear medicine and molecular imaging by supporting the practice and application of nuclear medicine. The first project focused on standardization of administered activities in pediatric nuclear medicine and resulted in two manuscripts. For its second project the NMGI chose to explore issues impacting on access and availability of radiopharmaceuticals around the world. Methods: Information was obtained by survey responses from 35 countries on available radioisotopes, radiopharmaceuticals and kits for diagnostic and therapeutic use. Issues impacting on access and availability of radiopharmaceuticals in individual countries were also identified. Results: Detailed information on radiopharmaceuticals utilized in each country, and sources of supply, was evaluated. Responses highlighted problems in access particularly due to the reliance on a sole provider, regulatory issues and reimbursement, as well as issues of facilities and workforce particularly in low- and middle-income countries. Conclusion: Finally, strategies to address access and availability of radiopharmaceuticals are outlined, to enable timely and equitable patient access to nuclear medicine procedures worldwide. In the face of disruptions to global supply chains by the COVID-19 outbreak, renewed focus on ensuring reliable supply of radiopharmaceuticals is a major priority for nuclear medicine practice globally.

43 PARTICLE ACCELERATORS↗

Economics of new molecular targeted personalized radiopharmaceuticals

We report that Nuclear Medicine has come a long way since 2007 when Adrian Nunn pointed out the approval of radiopharmaceuticals was at an all-time low with all the major radiopharmaceutical agents in use having been approved over 10 years ago. Challenges being the prohibitively high cost of drug development and the large number of drugs failing in clinical trials. Proceed to today where Molecular imaging is fast-tracking the drug discovery process by reducing both the time and cost to screen candidates by quantitating the drugs effect on the target and toxicity to normal tissues. Additionally, nuclear medicine is now leading medical practice in personalized medicine using the theragnostic approach. Theragnostics is defined as the use of molecular diagnostic techniques in real-time to stratify patients to guide treatment decisions such as the choice of drug, the dose of administration and the timing of drug delivery for a given patient. Enabling visualization and quantitation of in vivo function of the whole body and thus patient heterogeneity and variability informs the physician on how to treat an individual patient. Recent successes such as the FDA approval of Luta Thera® and NETSPOT™ have resulted in an increasing number of pharmaceutical companies pursing theragnostics further heightened by the purchase of Advanced Accelerator Applications for 3.9 billion by Novartis and Endocyte, Inc for 2.1 billion. Theragnostics are further aiding drug development by showing which agents are most viable and reducing the overall cost of bringing a drug to clinical trials and regulatory approval. This is indeed a renaissance for nuclear medicine in which the acceptance of imaging to inform and monitor therapy has been embraced and even required by the FDA for the clinical evaluation of targeted therapeutic radiopharmaceuticals showing there is indeed a viable business model for targeted theragnostic radiopharmaceuticals and personalized medicine.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Synthesis of DOTA-Based 43 Sc Radiopharmaceuticals Using Cyclotron-Produced 43 Sc as Exemplified by [ 43 Sc]Sc-PSMA-617 for PSMA PET Imaging

The implementation of theranostics in oncologic nuclear medicine has exhibited immense potential in improving patient outcomes in prostate cancer with the implementation of [ 68 Ga]Ga-PSMA-11 PET and [ 177 Lu]Lu-PSMA-617 into clinical practice. However, the correlation between radiopharmaceutical biodistributions seen with [ 68 Ga]Ga-PSMA-11 PET imaging and downstream [ 177 Lu]Lu-PSMA-617 therapy remains imperfect. This suggests that prostate cancer theranostics could potentially be further refined through the implementation of true theranostics, tandem pairs of diagnostic and therapeutic radiopharmaceuticals that utilize the same ligand and element, thus yielding identical pharmacokinetics. The radioscandiums are one such group of true theranostic radiopharmaceuticals. The radioscandiums consist of two β+ emitting scandium isotopes ( 43 Sc/ 44 Sc), as well as a β − emitting therapeutic isotope ( 47 Sc), which can all conjugate with PSMA-targeting PSMA-617. This potential has led to extensive investigations into the production of the radioscandiums as well as pre-clinical assessments with several ligands; however, there is a lack of literature extensively describing the complete synthesis of scandium radiopharmaceuticals. which therefore limits the accessibility of radioscandium research in theranostics. As such, this work aims to present an easily translatable protocol for the synthesis of [ 43 Sc]Sc-PSMA-617 from a [ 42 Ca]CaCO 3 starting material, including target formation, nuclear production via 42 Ca(d,n) 43 Sc reaction, chemical separation, radiolabeling, solvent reformulation, and target recycling.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Production of GMP-Compliant Clinical Amounts of Copper-61 Radiopharmaceuticals from Liquid Targets

PET imaging has gained significant momentum in the last few years, especially in the area of oncology, with an increasing focus on metal radioisotopes owing to their versatile chemistry and favourable physical properties. Copper-61 (t1/2 = 3.33 h, 61% β+, Emax = 1.216 MeV) provides unique advantages versus the current clinical standard (i.e., gallium-68) even though, until now, no clinical amounts of 61Cu-based radiopharmaceuticals, other than thiosemicarbazone-based molecules, have been produced. This study aimed to establish a routine production, using a standard medical cyclotron, for a series of widely used somatostatin analogues, currently labelled with gallium-68, that could benefit from the improved characteristics of copper-61. We describe two possible routes to produce the radiopharmaceutical precursor, either from natural zinc or enriched zinc-64 liquid targets and further synthesis of [61Cu]Cu-DOTA-NOC, [61Cu]Cu-DOTA-TOC and [61Cu]Cu-DOTA-TATE with a fully automated GMP-compliant process. The production from enriched targets leads to twice the amount of activity (3.28 ± 0.41 GBq vs. 1.84 ± 0.24 GBq at EOB) and higher radionuclidic purity (99.97% vs. 98.49% at EOB). Our results demonstrate, for the first time, that clinical doses of 61Cu-based radiopharmaceuticals can easily be obtained in centres with a typical biomedical cyclotron optimised to produce 18F-based radiopharmaceuticals.

Fonseca, Alexandra I. (ORCID:000000031924178X)↗

Consensus nomenclature rules for radiopharmaceutical chemistry — Setting the record straight

Over recent years, within the community of radiopharmaceutical sciences, there has been an increased incidence of incorrect usage of established scientific terms and conventions, and even the emergence of ‘self-invented’ terms. Here, in order to address these concerns, an international Working Group on ‘Nomenclature in Radiopharmaceutical Chemistry and related areas’ was established in 2015 to achieve clarification of terms and to generate consensus on the utilisation of a standardised nomenclature pertinent to the field. Upon open consultation, the following consensus guidelines were agreed, which aim to: Provide a reference source for nomenclature good practice in the radiopharma-ceutical sciences; Clarify the use of terms and rules concerning exclusively radiopharmaceutical terminology, i.e. nuclear- and radiochemical terms, symbols and expressions; Address gaps and inconsistencies in existing radiochemistry nomenclature rules; Provide source literature for further harmonisation beyond our immediate peer group (publishers, editors, IUPAC, pharmacopoeias, etc.).

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEA↗

Rhenium-188 Labeled Radiopharmaceuticals: Current Clinical Applications in Oncology and Promising Perspectives

Rhenium-188 ( 188 Re) is a high energy beta-emitting radioisotope with a short 16.9 h physical half-life, which has been shown to be a very attractive candidate for use in therapeutic nuclear medicine. The high beta emission has an average energy of 784 keV and a maximum energy of 2.12 MeV, sufficient to penetrate and destroy targeted abnormal tissues. In addition, the low-abundant gamma emission of 155 keV (15%) is efficient for imaging and for dosimetric calculations. These key characteristics identify 188 Re as an important therapeutic radioisotope for routine clinical use. Moreover, the highly reproducible on-demand availability of 188 Re from the 188 W/ 188 Re generator system is an important feature and permits installation in hospital-based or central radiopharmacies for cost-effective availability of no-carrier-added (NCA) 188 Re. Rhenium-188 and technetium-99 m exhibit similar chemical properties and represent a “theranostic pair.” Thus, preparation and targeting of 188 Re agents for therapy is similar to imaging agents prepared with 99m Tc, the most commonly used diagnostic radionuclide. Over the last three decades, radiopharmaceuticals based on 188 Re-labeled small molecules, including peptides, antibodies, Lipiodol and particulates have been reported. The successful application of these 188 Re-labeled therapeutic radiopharmaceuticals has been reported in multiple early phase clinical trials for the management of various primary tumors, bone metastasis, rheumatoid arthritis, and endocoronary interventions. This article reviews the use of 188 Re-radiopharmaceuticals which have been investigated in patients for cancer treatment, demonstrating that 188Re represents a cost effective alternative for routine clinical use in comparison to more expensive and/or less readily available therapeutic radioisotopes.

radiopharmaceuticals↗

Chelators and metal complex stability for radiopharmaceutical applications

Abstract Diagnostic and therapeutic nuclear medicine relies heavily on radiometal nuclides. The most widely used and well-known radionuclide is technetium-99m ( 99m Tc), which has dominated diagnostic nuclear medicine since the advent of the 99 Mo/ 99m Tc generator in the 1960s. Since that time, many more radiometals have been developed and incorporated into potential radiopharmaceuticals. One critical aspect of radiometal-containing radiopharmaceuticals is their stability under in vivo conditions. The chelator that is coordinated to the radiometal is a key factor in determining radiometal complex stability. The chelators that have shown the most promise and are under investigation in the development of diagnostic and therapeutic radiopharmaceuticals over the last 5 years are discussed in this review.

Chemistry↗

Detection of long-lived contaminants in cyclotron-produced radiopharmaceuticals by large area plastic scintillators

In the USA during 2015 over 1,718,500 clinical PET scans were performed in 2380 centers. Patients undergoing these studies will alarm homeland security monitors at borders, ports, and some airports for up to 2 days due to the positron-annihilation photons (0.511 MeV) from the imaging isotope 18 F (110 min half-life). In some radiopharmaceuticals, long-lived contaminants generated from the activation and spallation of elements in the HAVAR window of the cyclotron target may also be present in the patient dose. In this work, we have modeled a typical homeland security portal monitor in MCNP, and determined its sensitivity to each of the possible contaminating isotopes found in PET radiopharmaceuticals when distributed in patient phantoms. Furthermore, these data were combined with the time-dependent uptake/retention functions for the contaminating isotopes, to identify the isotopes that can cause alarms for substantial periods of time after the short-lived imaging agent has decayed away.

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEA↗

Automated cassette-based production of high specific activity [ 203/212 Pb]peptide-based theranostic radiopharmaceuticals for image-guided radionuclide therapy for cancer

A method for preparation of Pb-212 and Pb-203 labeled chelator-modified peptide-based radiopharmaceuticals for cancer imaging and radionuclide therapy has been developed and adapted for automated clinical production. Pre-concentration and isolation of radioactive Pb2+ from interfering metals in dilute hydrochloric acid was optimized using a commercially-available Pb-specific chromatography resin packed in disposable plastic columns. The pre-concentrated radioactive Pb2+ is eluted in NaOAc buffer directly to the reaction vessel containing chelator-modified peptides. Radiolabeling was found to proceed efficiently at 85 °C (45 min; pH 5.5). The specific activity of radiolabeled conjugates was optimized by separation of radiolabeled conjugates from unlabeled peptide via HPLC. Preservation of bioactivity was confirmed by in vivo biodistribution of Pb-203 and Pb-212 labeled peptides in melanoma-tumor-bearing mice. The approach has been found to be robustly adaptable to automation and a cassette-based fluid-handling system (Modular Lab Pharm Tracer) has been customized for clinical radiopharmaceutical production. Our findings demonstrate that the Pb-203/Pb-212 combination is a promising elementally-matched radionuclide pair for image-guided radionuclide therapy for melanoma, neuroendocrine tumors, and potentially other cancers.

59 BASIC BIOLOGICAL SCIENCES↗

Current Status of Radiopharmaceutical Therapy

In radiopharmaceutical therapy (RPT), a radionuclide is systemically or locally delivered with the goal of targeting and delivering radiation to cancer cells while minimizing radiation exposure to untargeted cells. Examples of current RPTs include thyroid ablation with the administration of {sup 131}I, treatment of liver cancer with {sup 90}Y microspheres, the treatment of bony metastases with {sup 223}Ra, and the treatment of neuroendocrine tumors with {sup 177}Lu-DOTATATE. New RPTs are being developed where radionuclides are incorporated into systemic targeted therapies. To assure that RPT is appropriately implemented, advances in targeting need to be matched with advances in quantitative imaging and dosimetry methods. Currently, radiopharmaceutical therapy is administered by intravenous or locoregional injection, and the treatment planning has typically been implemented like chemotherapy, where the activity administered is either fixed or based on a patient’s body weight or body surface area. RPT pharmacokinetics are measurable by quantitative imaging and are known to vary across patients, both in tumors and normal tissues. Therefore, fixed or weight-based activity prescriptions are not currently optimized to deliver a cytotoxic dose to targets while remaining within the tolerance dose of organs at risk. Methods that provide dose estimates to individual patients rather than to reference geometries are needed to assess and adjust the injected RPT dose. Accurate doses to targets and organs at risk will benefit the individual patients and decrease uncertainties in clinical trials. Imaging can be used to measure activity distribution in vivo, and this information can be used to determine patient-specific treatment plans where the dose to the targets and organs at risk can be calculated. The development and adoption of imaging-based dosimetry methods is particularly beneficial in early clinical trials. In this work we discuss dosimetric accuracy needs in modern radiation oncology, uncertainties in the dosimetry in RPT, and best approaches for imaging and dosimetry of internal radionuclide therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Study of potential utility of new radiopharmaceuticals based on technetium-99m labeled derivative of glucose

Purpose: to study the potential utility of 1-thio-D-glucose labeled with {sup 99m}Tc for cancer imaging in laboratory animals. Materials and method: the study was carried out in cell cultures of normal CHO (Chinese hamster ovary cells CHO) and malignant tissues MCF-7 (human breast adenocarcinoma MCF-7). To evaluate the uptake of {sup 99m}Tc-1-thio-D-glucose in normal and tumor tissue cells, 25 MBq of 1-thio-D-glucose labeled with {sup 99m}Tc was added to the vials with 3 million cells and incubated for 30 min at room temperature. After centrifugation of the vials with cells, the supernatant was removed. The radioactivity in vials with normal and tumor cells was then measured. In addition, the study included 40 mice of C57B1/6j lines with tumor lesion of the right femur. For neoplastic lesions, Lewis lung carcinoma model was used. Following anesthesia, mice were injected intravenously with 25 MBq of {sup 99m}Tc-1-thio-D-glucose. Planar scintigraphy was performed 15 minutes later in a matrix of 512x512 pixels for 5 min. Results: when measuring the radioactivity of normal and malignant cells after incubation with {sup 99m}Tc-1-thio-D-glucose, it was found that the radioactivity of malignant cells was higher than that of normal cells. The mean values of radioactivity levels in normal and malignant cells were 0.3 ± 0.15 MBq and 1.07 ± 0.6 MBq, respectively. All examined animals had increased accumulation of {sup 99m}Tc-1-thio-D-glucose at the tumor site. The accumulation of {sup 99m}Tc-1-thio-D-glucose in the tumor was on average twice as high as compared to the symmetric region. Conclusion: The present study demonstrated that {sup 99m}Tc-1-thio-D-glucose is a prospective radiopharmaceutical for cancer visualization. In addition, high accumulation of {sup 99m}Tc-1-thio-D-glucose in the culture of cancer cells and in tumor tissue of animals demonstrates tumor tropism of the radiopharmaceutical.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Development of radiopharmaceuticals for targeted alpha therapy: Where do we stand?

Targeted alpha therapy is an oncological treatment, where cytotoxic doses of alpha radiation are locally delivered to tumor cells, while the surrounding healthy tissue is minimally affected. This therapeutic strategy relies on radiopharmaceuticals made of medically relevant radionuclides chelated by ligands, and conjugated to targeting vectors, which promote the drug accumulation in tumor sites. This review discusses the state-of-the-art in the development of radiopharmaceuticals for targeted alpha therapy, breaking down their key structural components, such as radioisotope, targeting vector, and delivery formulation, and analyzing their pros and cons. Moreover, we discuss current drawbacks that are holding back targeted alpha therapy in the clinic, and identify ongoing strategies in field to overcome those issues, including radioisotope encapsulation in nanoformulations to prevent the release of the daughters. Lastly, we critically discuss potential opportunities the field holds, which may contribute to targeted alpha therapy becoming a gold standard treatment in oncology in the future.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Coded aperture and Compton imaging for the development of 225 Ac‐based radiopharmaceuticals

Abstract Background Targeted alpha‐particle therapy (TAT) has great promise as a cancer treatment. Arguably the most promising TAT radionuclide that has been proposed is 225 Ac. The development of 225 Ac‐based radiopharmaceuticals has been hampered due to the lack of effective means to study the daughter redistribution of these agents in small animals at the preclinical stage. Purpose The ability to directly image the daughters, namely 221 Fr and 213 Bi, via their gamma‐ray emissions would be a boon for preclinical studies. That said, conventional medical imaging modalities, including single photon emission computed tomography (SPECT) based on nonmultiplexed collimation, cannot be employed due to sensitivity limitations. Methods As an alternative, we propose the use of both coded aperture and Compton imaging with the former modality suited to the 218‐keV gamma‐ray emission of 221 Fr and the latter suited to the 440‐keV gamma‐ray emission of 213 Bi. Results This work includes coded aperture images of 221 Fr and Compton images of 213 Bi in tumor‐bearing mice injected with 225 Ac‐based radiopharmaceuticals. Conclusions These results are the first demonstration of visualizing and quantifying the 225 Ac daughters in small animals through the application of coded aperture and Compton imaging.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

CD46-Targeted Theranostics for PET and 225 Ac-Radiopharmaceutical Therapy of Multiple Myeloma

Multiple myeloma is a plasma cell malignancy with an unmet clinical need for improved imaging methods and therapeutics. Recently, we identified CD46 as an overexpressed therapeutic target in multiple myeloma and developed the antibody YS5, which targets a cancer-specific epitope on this protein. We further developed the CD46-targeting PET probe [ 89 Zr]Zr-DFO-YS5 for imaging and [ 225 Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of prostate cancer. These prior studies suggested the feasibility of the CD46 antigen as a theranostic target in multiple myeloma. Herein, we validate [ 89 Zr]Zr-DFO-YS5 for immunoPET imaging and [ 225 Ac]Ac-DOTA-YS5 for radiopharmaceutical therapy of multiple myeloma in murine models. In vitro saturation binding was performed using the CD46 expressing MM.1S multiple myeloma cell line. ImmunoPET imaging using [ 89 Zr]Zr-DFO-YS5 was performed in immunodeficient (NSG) mice bearing subcutaneous and systemic multiple myeloma xenografts. For radioligand therapy, [ 225 Ac]Ac-DOTA-YS5 was prepared, and both dose escalation and fractionated dose treatment studies were performed in mice bearing MM1.S-Luc systemic xenografts. Tumor burden was analyzed using BLI, and body weight and overall survival were recorded to assess antitumor effect and toxicity. [ 89 Zr]Zr-DFO-YS5 demonstrated high affinity for CD46 expressing MM.1S multiple myeloma cells (K d = 16.3 nmol/L). In vitro assays in multiple myeloma cell lines demonstrated high binding, and bioinformatics analysis of human multiple myeloma samples revealed high CD46 expression. [ 89 Zr]Zr-DFO-YS5 PET/CT specifically detected multiple myeloma lesions in a variety of models, with low uptake in controls, including CD46 knockout (KO) mice or multiple myeloma mice using a nontargeted antibody. In the MM.1S systemic model, localization of uptake on PET imaging correlated well with the luciferase expression from tumor cells. A treatment study using [ 225 Ac]Ac-DOTA-YS5 in the MM.1S systemic model demonstrated a clear tumor volume and survival benefit in the treated groups. Our study showed that the CD46-targeted probe [ 89 Zr]Zr-DFO-YS5 can successfully image CD46-expressing multiple myeloma xenografts in murine models, and [ 225 Ac]Ac-DOTA-YS5 can effectively inhibit the growth of multiple myeloma. These results demonstrate that CD46 is a promising theranostic target for multiple myeloma, with the potential for clinical translation.

59 BASIC BIOLOGICAL SCIENCES↗

Production and purification of research scale 161 Tb using cation-exchange semi-preparative HPLC for radiopharmaceutical applications

Terbium-161 ( 161 Tb) is emerging as a promising radionuclide for cancer therapy due to its favorable nuclear properties that are similar to clinically established lutetium-177 ( 177 Lu) along with its therapeutic edge arising from the higher number of Auger and conversion electrons per decay. These low energy electrons result in higher cytotoxicity within a short range of the decaying nuclei to enhance therapeutic efficacy. Despite these promising characteristics, a significant challenge remains in the lack of a domestic 161 Tb supply in the United States, which poses an obstacle to the advancement of 161 Tb-based radiopharmaceutical research and development. Here, this study developed a reliable cation-exchange high-performance liquid chromatography-based method for purification of reactor-produced 161 Tb at quantities suitable to support research and preclinical studies. The purified 161 Tb product showed high radionuclidic purity with excellent radiochemical purity, and the successful labeling studies with the DOTA chelator and DOTA-TATE peptide demonstrated the effective incorporation of the purified 161 Tb into radiopharmaceuticals designed for targeted cancer therapy.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

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

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

Pharmacology & Pharmacy↗