Actinium-225 photonuclear production in nuclear reactors using a mixed radium-226 and gadolinium-157 target.

BACKGROUND: Actinium-225 is one of the most promising radionuclides for targeted alpha therapy. Its limited availability significantly restricts clinical trials and potential applications of 225Ac-based radiopharmaceuticals. METHODS: In this work, we examine the possibility of 225Ac production from the thermal neutron flux of a nuclear reactor. For this purpose, a target consisting of 1.4 mg of 226Ra(NO3)2 (T1/2 = 1600 years) and 115.5 mg of 90 % enriched, stable 157Gd2O3 was irradiated for 48 h in the Breazeale Nuclear Reactor with an average neutron flux of 1.7·1013 cm-2·s-1. Gadolinium-157 has one of the highest thermal neutron capture cross sections of 0.25 Mb, and its neutron capture results in emission of high-energy, prompt γ-photons. Emitted γ-photons interact with 226Ra to produce 225Ra according to the 226Ra(γ, n)225Ra reaction. Gadolinium debulking and separation of undesirable, co-produced 227Ac from 225Ra was achieved in one step by using 60 g of branched DGA resin. After 225Ac ingrowth from 225Ra (T1/2 = 14.8 d), 225Ac was extracted from the 226Ra and 225Ra fraction using 5 g of bDGA resin and then eluted using 5 mM HNO3. RESULTS: Measured activity of 225Ac showed that 6(1) kBq or 0.16(3) µCi (1σ) of 225Ra was produced at the end of bombardment from 0.9 mg of 226Ra. CONCLUSION: The developed 225Ac separation is a waste-free process which can be used to obtain pure 225Ac in a nuclear reactor.

Evaluation of a bimodal, matched pair theranostic agent targeting prostate-specific membrane antigen.

BACKGROUND: Prostate cancer affects 1 in 6 men, and it is the second­leading cause of cancer-related death in American men. Surgery is one of the main treatment modalities for prostate cancer, but it often results in incomplete resection margins or complete resection that leads to nerve damage and undesirable side effects. In the present work, we have developed a new bimodal tracer, NODAGA-sCy7.5 PSMAi (prostate-specific membrane antigen inhibitor), labeled with the true matched theranostic pair 64Cu/67Cu and a near-infrared fluorescent dye. This agent could potentially be used for concomitant PET imaging, optical surgical navigation, and targeted radiopharmaceutical therapy. METHODS: A prostate-specific membrane antigen (PSMA)-targeting urea derivative was conjugated to NODAGA for copper radiolabeling and to the near-infrared fluorophore sulfo-Cy7.5 (sCy7.5). Binding studies were performed in PSMA-positive PC-3 PIP cells, as well as uptake and internalization assays in PC-3 PIP cells and PSMA-negative PC-3 wild type cells. Biodistribution studies of the 64Cu-labeled compound were performed in PC-3 PIP- and PC-3 tumor-bearing mice, and 67Cu biodistributions of the agent were obtained in PC-3 PIP tumor-carrying mice. PET imaging and fluorescence imaging were also performed, using the same molar doses, in the two mouse models. RESULTS: The PSMA conjugate bound with high affinity to PSMA-positive prostate cancer cells, as opposed to cells that were PSMA-negative. Uptake and internalization were rapid and PSMA-mediated in PC-3 PIP cells, while only minimal non-specific uptake was observed in PC-3 cells. Biodistribution studies showed specific uptake in PC-3 PIP tumors, while accumulation in PC-3 tumor-bearing mice was low. Furthermore, tumor uptake of the 67Cu-labeled agent in the PC-3 PIP model was statistically equivalent to that of 64Cu. PET and fluorescence imaging at 0.5 nmol per mouse also demonstrated that PC-3 PIP tumors could be clearly detected, while PC-3 tumors showed no tumor accumulation. CONCLUSIONS: NODAGA-sCy7.5-PSMAi was specific and selective in detecting PSMA-positive, as opposed to PSMA-negative, tumors in mouse models of prostate cancer. This bioconjugate could potentially be used for PET staging with 64Cu, targeted radiopharmaceutical therapy with 67Cu, and/or image-guided surgery with sCy7.5.

Monte Carlo-Based Nanoscale Dosimetry Holds Promise for Radiopharmaceutical Therapy Involving Auger Electron Emitters.

Radiopharmaceutical therapy (RPT) is evolving as a promising strategy for treating cancer. As interest grows in short-range particles, like Auger electrons, understanding the dose-response relationship at the deoxyribonucleic acid (DNA) level has become essential. In this study, we used the Geant4-DNA toolkit to evaluate DNA damage caused by the Auger-electron-emitting isotope I-125. We compared the energy deposition and single strand break (SSB) yield at each base pair location in a short B-form DNA (B-DNA) geometry with existing simulation and experimental data, considering both physical direct and chemical indirect hits. Additionally, we evaluated dosimetric differences between our high-resolution B-DNA target and a previously published simple B-DNA geometry. Overall, our benchmarking results for SSB yield from I-125 decay exhibited good agreement with both simulation and experimental data. Using this simulation, we then evaluated the SSB and double strand break (DSB) yields caused by a theranostic Br-77-labeled poly ADP ribose polymerase (PARP) inhibitor radiopharmaceutical. The results indicated a predominant contribution of chemical indirect hits over physical direct hits in generating SSB and DSB. This study lays the foundation for future investigations into the nano-dosimetric properties of RPT.

Theranostic digital twins: Concept, framework and roadmap towards personalized radiopharmaceutical therapies.

Radiopharmaceutical therapy (RPT) is a rapidly developing field of nuclear medicine, with several RPTs already well established in the treatment of several different types of cancers. However, the current approaches to RPTs often follow a somewhat inflexible "one size fits all" paradigm, where patients are administered the same amount of radioactivity per cycle regardless of their individual characteristics and features. This approach fails to consider inter-patient variations in radiopharmacokinetics, radiation biology, and immunological factors, which can significantly impact treatment outcomes. To address this limitation, we propose the development of theranostic digital twins (TDTs) to personalize RPTs based on actual patient data. Our proposed roadmap outlines the steps needed to create and refine TDTs that can optimize radiation dose to tumors while minimizing toxicity to organs at risk. The TDT models incorporate physiologically-based radiopharmacokinetic (PBRPK) models, which are additionally linked to a radiobiological optimizer and an immunological modulator, taking into account factors that influence RPT response. By using TDT models, we envisage the ability to perform virtual clinical trials, selecting therapies towards improved treatment outcomes while minimizing risks associated with secondary effects. This framework could empower practitioners to ultimately develop tailored RPT solutions for subgroups and individual patients, thus improving the precision, accuracy, and efficacy of treatments while minimizing risks to patients. By incorporating TDT models into RPTs, we can pave the way for a new era of precision medicine in cancer treatment.

An International Study of Factors Affecting Variability of Dosimetry Calculations, Part 3: Contribution from Calculating Absorbed Dose from Time-Integrated Activity.

Image-based dosimetry-guided radiopharmaceutical therapy has the potential to personalize treatment by limiting toxicity to organs at risk and maximizing the therapeutic effect. The 177Lu dosimetry challenge of the Society of Nuclear Medicine and Molecular Imaging consisted of 5 tasks assessing the variability in the dosimetry workflow. The fifth task investigated the variability associated with the last step, dose conversion, of the dosimetry workflow on which this study is based. Methods: Reference variability was assessed by 2 medical physicists using different software, methods, and all possible combinations of input segmentation formats and time points as provided in the challenge. General descriptive statistics for absorbed dose values from the global submissions from participants were calculated, and variability was measured using the quartile coefficient of dispersion. Results: For the liver, which included lesions with high uptake, variabilities of up to 36% were found. The baseline analysis showed a variability of 29% in absorbed dose results for the liver from datasets where lesions included and excluded were grouped, indicating that variation in how lesions in normal liver were treated was a significant source of variability. For other organs and lesions, variability was within 7%, independently of software used except for the local deposition method. Conclusion: The choice of dosimetry method or software had a small contribution to the overall variability of dose estimates.

Enhanced Internal Dosimetry for Alimentary Tract Organs in Nuclear Medicine based on the ICRP Mesh-Type Reference Phantoms.

This study introduces a refined approach for more accurately estimating radiation doses to alimentary tract organs in nuclear medicine, by utilizing the ICRP pediatric and adult mesh-type reference computational phantoms (MRCPs) that improved the anatomical representation of these organs. Our initial step involved compiling a comprehensive dataset of electron Specific Absorbed Fractions (SAFs) for all source-target pairs of alimentary tract organs in both adult and pediatric phantoms, calculating SAFs for all cases in the present study only except those computed in the previous study for certain pediatric phantom cases. Subsequently, we determined S values for 1,252 radionuclides, facilitating dosimetry applications. The consistency of target and source masses for alimentary tract organs in the MRCPs with the reference values in ICRP Publication 89 led to noticeable differences in SAF, S values, and consequently, absorbed dose coefficients when compared to the stylized models in ICRP Publication 100. Notably, the S value ratios (MRCP/stylized) for selected radionuclides-11C, 18F, 68Ga, and 131I-ranged from 0.41 to 7.60. Particularly for therapeutic 131I-iodide in thyroid cancer, the use of MRCPs resulted in up to 1.49 times higher absorbed dose coefficients for the colon than those derived from stylized models, while the stomach dose coefficients decreased by a factor of 0.72. The application of our findings promises enhanced, more realistic dosimetry for alimentary tract organs, especially beneficial for radiopharmaceuticals likely to accumulate within these organs.

A PET probe targeting polyamine transport system for precise tumor diagnosis and therapy.

Polyamine metabolism dysregulation is a hallmark of many cancers, offering a promising avenue for early tumor theranostics. This study presents the development of a nuclear probe derived from spermidine (SPM) for dual-purpose tumor PET imaging and internal radiation therapy. The probe, radiolabeled with either [68Ga]Ga for diagnostic applications or [177Lu]Lu for therapeutic use, was synthesized with exceptional purity, stability, and specific activity. Extensive testing involving 12 different tumor cell lines revealed remarkable specificity towards B16 melanoma cells, showcasing outstanding tumor localization and target-to-non-target ratio. Mechanistic investigations employing polyamines, non-labeled precursor, and polyamine transport system (PTS) inhibitor, consistently affirmed the probe's targetability through recognition of the PTS. Notably, while previous reports indicated PTS upregulation in various tumor types for targeted therapy, this study observed no positive signals, highlighting a concentration-dependent discrepancy between targeting for therapy and diagnosis. Furthermore, when labeled with [177Lu], the probe demonstrated its therapeutic potential by effectively controlling tumor growth and extending mouse survival. Investigations into biodistribution, excretion, and biosafety in healthy humans laid a robust foundation for clinical translation. This study introduces a versatile SPM-based nuclear probe with applications in precise tumor theranostics, offering promising prospects for clinical implementation.

The MIRD Schema for Radiopharmaceutical Dosimetry: A Review.

Internal dosimetry evaluates the amount and spatial and temporal distributions of radiation energy deposited in tissue from radionuclides within the body. Historically, nuclear medicine had been largely a diagnostic specialty, and the implicitly performed risk-benefit analyses have been straightforward, with relatively low administered activities yielding important diagnostic information whose benefit far outweighs any potential risk associated with the attendant normal-tissue radiation doses. Although dose estimates based on anatomic models and population-average kinetics in this setting may deviate rather significantly from the actual normal-organ doses for individual patients, the large benefit-to-risk ratios are very forgiving of any such inaccuracies. It is in this context that the MIRD schema was originally developed and has been largely applied. The MIRD schema, created and maintained by the MIRD committee of the Society of Nuclear Medicine and Molecular Imaging, comprises the notation, terminology, mathematic formulas, and reference data for calculating tissue radiation doses from radiopharmaceuticals administered to patients. However, with the ongoing development of new radiopharmaceuticals and the increasing therapeutic application of such agents, internal dosimetry in nuclear medicine and the MIRD schema continue to evolve-from population-average and organ-level to patient-specific and suborgan to voxel-level to cell-level dose estimation. This article will review the basic MIRD schema, relevant quantities and units, reference anatomic models, and its adaptation to small-scale and patient-specific dosimetry.

cGMP compliant one-step, one-pot automated [18F]FBnTP production for clinical imaging of mitochondrial activity.

BACKGROUND: 4-[18F]fluorobenzyl-triphenylphosphonium ([18F]FBnTP) is a lipophilic cation PET tracer. The cellular uptake of [18F]FBnTP is correlated with oxidative phosphorylation by mitochondria, which has been associated with multiple critical diseases. To date, [18F]FBnTP has been successfully applied for imaging myocardial perfusion, assessment of severity of coronary artery stenosis, delineation of the ischemic area after transient coronary occlusion, and detection/quantification of apoptosis in various animal models. Recent preclinical and clinical studies have also expanded the possibilities of using [18F]FBnTP in oncological diagnosis and therapeutic monitoring. However, [18F]FBnTP is typically prepared through a tediously lengthy four-step, three-pot reaction and required multiple synthesizer modules; Thus, such an approach remains a challenge for this promising radiopharmaceutical to be implemented for routine clinical studies. Herein, we report an optimized one-step, one-pot automated approach to produce [18F]FBnTP through a single standard commercially-available radiosynthesizer that enables centralized production for clinical use. RESULTS: The fully automated production of [18F]FBnTP took less than 55 min with radiochemical yields ranging from 28.33 ± 13.92% (non-decay corrected), apparent molar activity of 69.23 ± 45.62 GBq/µmol, and radiochemical purities of 99.79 ± 0.41%. The formulated [18F]FBnTP solution was determined to be sterile and colorless with a pH of 4.0-6.0. Our data has indicated no observable radiolysis after 8 h from the time of final product formulation and maximum assay of 7.88 GBq. CONCLUSIONS: A simplified and cGMP-compliant radiosynthesis of [18F]FBnTP has been established on the commercially available synthesizer in high activity concentration and radiochemical purity. While the preclinical and clinical studies using [18F]FBnTP PET are currently underway, the automated approaches reported herein facilitate clinical adoption of this radiotracer and warrant centralized production of [18F]FBnTP for imaging multiple patients.

11C-methionine in the diagnostics and management of glioblastoma patients with rapid early progression: nonrandomized, open label, prospective clinical trial (GlioMET).

BACKGROUND: Glioblastoma (GBM) is the most common and aggressive primary brain cancer. The treatment of GBM consists of a combination of surgery and subsequent oncological therapy, i.e., radiotherapy, chemotherapy, or their combination. If postoperative oncological therapy involves irradiation, magnetic resonance imaging (MRI) is used for radiotherapy treatment planning. Unfortunately, in some cases, a very early worsening (progression) or return (recurrence) of the disease is observed several weeks after the surgery and is called rapid early progression (REP). Radiotherapy planning is currently based on MRI for target volumes definitions in many radiotherapy facilities. However, patients with REP may benefit from targeting radiotherapy with other imaging modalities. The purpose of the presented clinical trial is to evaluate the utility of 11C-methionine in optimizing radiotherapy for glioblastoma patients with REP. METHODS: This study is a nonrandomized, open-label, parallel-setting, prospective, monocentric clinical trial. The main aim of this study was to refine the diagnosis in patients with GBM with REP and to optimize subsequent radiotherapy planning. Glioblastoma patients who develop REP within approximately 6 weeks after surgery will undergo 11C-methionine positron emission tomography (PET/CT) examinations. Target volumes for radiotherapy are defined using both standard planning T1-weighted contrast-enhanced MRI and PET/CT. The primary outcome is progression-free survival defined using RANO criteria and compared to a historical cohort with REP treated without PET/CT optimization of radiotherapy. DISCUSSION: PET is one of the most modern methods of molecular imaging. 11C-Methionine is an example of a radiolabelled (carbon 11) amino acid commonly used in the diagnosis of brain tumors and in the evaluation of response to treatment. Optimized radiotherapy may also have the potential to cover those regions with a high risk of subsequent progression, which would not be identified using standard-of-care MRI for radiotherapy planning. This is one of the first study focused on radiotherapy optimization for subgroup of patinets with REP. TRIAL REGISTRATION: NCT05608395, registered on 8.11.2022 in clinicaltrials.gov; EudraCT Number: 2020-000640-64, registered on 26.5.2020 in clinicaltrialsregister.eu. Protocol ID: MOU-2020-01, version 3.2, date 18.09.2020.

Aurora Kinase A inhibition enhances DNA damage and tumor cell death with 131I-MIBG therapy in high-risk neuroblastoma.

BACKGROUND: Neuroblastoma is the most common extra-cranial pediatric solid tumor. 131I-metaiodobenzylguanidine (MIBG) is a targeted radiopharmaceutical highly specific for neuroblastoma tumors, providing potent radiotherapy to widely metastatic disease. Aurora kinase A (AURKA) plays a role in mitosis and stabilization of the MYCN protein in neuroblastoma. We aimed to study the impact of AURKA inhibitors on DNA damage and tumor cell death in combination with 131I-MIBG therapy in a pre-clinical model of high-risk neuroblastoma. RESULTS: Using an in vivo model of high-risk neuroblastoma, we demonstrated a marked combinatorial effect of 131I-MIBG and alisertib on tumor growth. In MYCN amplified cell lines, the combination of radiation and an AURKA A inhibitor increased DNA damage and apoptosis and decreased MYCN protein levels. CONCLUSION: The combination of AURKA inhibition with 131I-MIBG treatment is active in resistant neuroblastoma models.

A step toward simplified dosimetry of radiopharmaceutical therapy via SPECT frame duration reduction.

Despite being time-consuming, SPECT/CT data is necessary for accurate dosimetry in patient-specific radiopharmaceutical therapy. We investigated how reducing the frame duration (FD) during SPECT acquisition can simplify the dosimetry workflow for [177Lu]Lu-PSMA radioligand therapy (RLT). We aimed to determine the impact of shortened acquisition times on dosimetric precision. Three SPECT scans with FD of 20, 10, and 5 second/frame (sec/fr) were obtained 48 h post-RLT from one metastatic castration-resistant prostate cancer (mCRPC) patient's pelvis. Planar images at 4, 48, and 72 h post-therapy were used to calculate time-integrated activities (TIAs). Using accurate activity calibrations and GATE Monte Carlo (MC) dosimetry, absorbed doses in tumor lesions and kidneys were estimated. Dosimetry precision was assessed by comparing shorter FD results to the 20 sec/fr reference using relative percentage difference (RPD). We observed consistent calibration factors (CFs) across different FDs. Using the same CF, we obtained marginal RPD deviations less than 4% for the right kidney and tumor lesions and less than 7% for the left kidney. By reducing FD, simulation time was slightly decreased. This study shows we can shorten SPECT acquisition time in RLT dosimetry by reducing FD without sacrificing dosimetry accuracy. These findings pave the way for streamlined personalized internal dosimetry workflows.

Assessing Response to PSMA Radiopharmaceutical Therapies with Single SPECT Imaging at 24 Hours After Injection.

Understanding the relationship between lesion-absorbed dose and tumor response in 177Lu-PSMA-617 radiopharmaceutical therapies (RPTs) remains complex. We aimed to investigate whether baseline lesion-absorbed dose can predict lesion-based responses and to explore the connection between lesion-absorbed dose and prostate-specific antigen (PSA) response. Methods: In this retrospective study, we evaluated 50 patients with 335 index lesions undergoing 177Lu-PSMA-617 RPT, who had dosimetry analysis performed on SPECT/CT at 24 h after cycles 1 and 2. First, we identified the index lesions for each patient and measured the lesion-based absorbed doses. Lesion-based response was calculated after cycle 2. Additionally, PSA50 response (a decline of 50% from baseline PSA) after cycle 2 was also calculated. The respective responses for mean and maximum absorbed doses and prostate-specific membrane antigen (PSMA) volumetric intensity product (VIP-PSMA) at cycles 1 and 2 were termed SPECTmean, SPECTmaximum, and SPECTVIP-PSMA, respectively. Results: Of the 50 patients reviewed, 46% achieved a PSA50 response after cycle 2. Of the 335 index lesions, 58% were osseous, 32% were lymph nodes, and 10% were soft-tissue metastatic lesions. The SPECT lesion-based responses were higher in PSA responders than in nonresponders (SPECTmean response of 46.8% ± 26.1% vs. 26.2% ± 24.5%, P = 0.007; SPECTmaximum response of 45% ± 25.1% vs. 19% ± 27.0%, P = 0.001; SPECTVIP-PSMA response of 49.2% ± 30.3% vs. 14% ± 34.7%, P = 0.0005). An association was observed between PSA response and SPECTVIP-PSMA response (R 2 = 0.40 and P < 0.0001). A limited relationship was found between baseline absorbed dose measured with a 24-h single time point and SPECT lesion-based response (R 2 = 0.05, P = 0.001, and R 2 = 0.03, P = 0.007, for mean and maximum absorbed doses, respectively). Conclusion: In this retrospective study, quantitative lesion-based response correlated with patient-level PSA response. We observed a limited relationship between baseline absorbed dose and lesion-based responses. Most of the variance in response remains unexplained solely by baseline absorbed dose. Establishment of a dose-response relationship in RPT with a single time point at 24 h presented some limitations.

Pre-therapy PET-based voxel-wise dosimetry prediction by characterizing intra-organ heterogeneity in PSMA-directed radiopharmaceutical theranostics.

BACKGROUND AND OBJECTIVE: Treatment planning through the diagnostic dimension of theranostics provides insights into predicting the absorbed dose of RPT, with the potential to individualize radiation doses for enhancing treatment efficacy. However, existing studies focusing on dose prediction from diagnostic data often rely on organ-level estimations, overlooking intra-organ variations. This study aims to characterize the intra-organ theranostic heterogeneity and utilize artificial intelligence techniques to localize them, i.e. to predict voxel-wise absorbed dose map based on pre-therapy PET. METHODS: 23 patients with metastatic castration-resistant prostate cancer treated with [177Lu]Lu-PSMA I&T RPT were retrospectively included. 48 treatment cycles with pre-treatment PET imaging and at least 3 post-therapeutic SPECT/CT imaging were selected. The distribution of PET tracer and RPT dose was compared for kidney, liver and spleen, characterizing intra-organ heterogeneity differences. Pharmacokinetic simulations were performed to enhance the understanding of the correlation. Two strategies were explored for pre-therapy voxel-wise dosimetry prediction: (1) organ-dose guided direct projection; (2) deep learning (DL)-based distribution prediction. Physical metrics, dose volume histogram (DVH) analysis, and identity plots were applied to investigate the predicted absorbed dose map. RESULTS: Inconsistent intra-organ patterns emerged between PET imaging and dose map, with moderate correlations existing in the kidney (r = 0.77), liver (r = 0.5), and spleen (r = 0.58) (P < 0.025). Simulation results indicated the intra-organ pharmacokinetic heterogeneity might explain this inconsistency. The DL-based method achieved a lower average voxel-wise normalized root mean squared error of 0.79 ± 0.27%, regarding to ground-truth dose map, outperforming the organ-dose guided projection (1.11 ± 0.57%) (P < 0.05). DVH analysis demonstrated good prediction accuracy (R2 = 0.92 for kidney). The DL model improved the mean slope of fitting lines in identity plots (199% for liver), when compared to the theoretical optimal results of the organ-dose approach. CONCLUSION: Our results demonstrated the intra-organ heterogeneity of pharmacokinetics may complicate pre-therapy dosimetry prediction. DL has the potential to bridge this gap for pre-therapy prediction of voxel-wise heterogeneous dose map.

Automated radiosynthesis of [11C]CPPC for in-human PET imaging applications.

The macrophage colony-stimulating factor 1 receptor (CSF1R) is almost exclusively expressed in microglia, representing a biomarker target for imaging of microglia availability. [11C]CPPC has specific binding affinity to CSF1R and suitable kinetic properties for in vivo PET imaging of microglia. However, previous studies reported a low radiochemical yield, motivating additional research to optimize [11C]CPPC radiochemistry. In this work, we report an automated radiosynthesis of [11C]CPPC on a Synthra MeIPlus module with improved radiochemical yield. The final [11C]CPPC product was obtained with excellent chemical/radiochemical purities and molecular activity, facilitating high-quality in-human PET imaging applications.

Radiopharmaceuticals for Skeletal Muscle PET Imaging.

The skeletal muscles account for approximately 40% of the body weight and are crucial in movement, nutrient absorption, and energy metabolism. Muscle loss and decline in function cause a decrease in the quality of life of patients and the elderly, leading to complications that require early diagnosis. Positron emission tomography/computed tomography (PET/CT) offers non-invasive, high-resolution visualization of tissues. It has emerged as a promising alternative to invasive diagnostic methods and is attracting attention as a tool for assessing muscle function and imaging muscle diseases. Effective imaging of muscle function and pathology relies on appropriate radiopharmaceuticals that target key aspects of muscle metabolism, such as glucose uptake, adenosine triphosphate (ATP) production, and the oxidation of fat and carbohydrates. In this review, we describe how [18F]fluoro-2-deoxy-D-glucose ([18F]FDG), [18F]fluorocholine ([18F]FCH), [11C]acetate, and [15O]water ([15O]H2O) are suitable radiopharmaceuticals for diagnostic imaging of skeletal muscles.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

BACKGROUND: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. MAIN BODY: This selection of highlights provides commentary on 24 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. CONCLUSION: Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects.

Alpha-emitter Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) has become mainstream therapy of metastatic neuroendocrine tumors not controlled by somatostatin analog therapy. Currently, beta particle-emitting radiopharmaceuticals are the mainstay of PRRT. Alpha particle-emitting radiopharmaceuticals have a theoretic advantage over beta emitters in terms of improved therapeutic efficacy due to higher cancer cell death and lower nontarget tissue radiation-induced adverse events due to shorter path length of alpha particles. We discuss the available evidence for and the role of alpha particle PRRT.

Short-Term Biological Toxicity Prediction of [177Lu]Lutetium-Oxodotreotide: An Original Retrospective Analysis.

Introduction: [177Lu]Lutetium (Lu)-oxodotreotide is a radiopharmaceutical drug used as peptide receptor radionuclide therapy (PRRT) for somatostatin receptor-expressing neuroendocrine neoplasms. It provides an additional effective alternative treatment for these rare cancers. Although well tolerated, its safety profile must continue to be characterized to support its use as a first-line treatment or for additional cycles. This study evaluated factors associated with the occurrence of [177Lu]Lu-oxodotreotide induced short-term toxicity. Materials and Methods: A retrospective observational monocentric study was carried out from July 2013 to October 2021. Inclusion criteria were defined as follows: patients who received at least four cycles of [177Lu]Lu-oxodotreotide and were followed up for 6 months after the last injection. Graduated toxicity was defined using the National Cancer Institute Common Terminology Criteria for Adverse Events 5.0. Cox regression was used in the analysis. Results: Forty patients were included. The most frequent toxicities occurred during the first cycle and were graded as G1 or G2. As expected, toxicities were predominantly hematological and hepatic, with incomplete reversibility after each cycle. The following factors were significantly related to the occurrence of hematological or hepatic toxicity during PRRT: gastrointestinal primary tumor diagnosis, bone metastases, peritoneal metastases, pancreatic metastases or pulmonary metastases, and high tumor grade. Conclusion: Knowledge and consideration of these factors in adjusting [177Lu]Lu-oxodotreotide treatment regimen could help prevent or reduce the severity of these toxicities. Further studies are still warranted to refine these results and improve treatment management.

Current state of theranostics in metastatic castrate-resistant prostate cancer.

Prostate cancer remains one of the leading causes of cancer-related death in the world. There have been significant advances in chemotherapy, hormonal therapy and targeted therapy options for patients with castrate-resistant disease. However, these systemic treatments are often associated with unwanted toxicities. Targeted therapy with radiopharmaceuticals has become of key interest to limit systemic toxicity and provides a more precision oncology approach to treatment. Strontium-89, Samarium-153 EDTMP and Radium-223 have been trialled with mixed results. Strontium-89 and Samarium-153 EDTMP have shown benefits in palliating metastatic bone pain but with no impact on survival outcomes. Early therapeutic radiopharmaceuticals targeting PSMA that were developed were beta-emitting agents, but recently alpha-emitting agents are being investigated as potentially superior options. Radium-223 is the first alpha-particle emitter therapeutic agent approved by the FDA, with phase III trial evidence showing benefits in overall survival and delay in symptomatic skeletal events for patients. Recently, 177-Lutetium-PSMA-617 has demonstrated significant survival advantages in pre-treated metastatic castrate-resistant cancer patients in a number of phase II and III studies. Furthermore, 225-Actinium-PSMA-617 also showed promise even in patients pre-treated with 177-Lutetium-PSMA-617. Hence, there has been an explosion of radiopharmaceutical treatment options for patients with prostate cancer. This review explores past and current theranostic capacities in the radiopharmaceutical treatment of metastatic castrate-resistant prostate cancer.