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.

Imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial.

BACKGROUND: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. METHODS: We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741. FINDINGS: Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. INTERPRETATION: DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. FUNDING: National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.

First in-human evaluation of [1-13C]pyruvate in D2O for hyperpolarized MRI of the brain: A safety and feasibility study.

PURPOSE: To investigate the safety and value of hyperpolarized (HP) MRI of [1-13C]pyruvate in healthy volunteers using deuterium oxide (D2O) as a solvent. METHODS: Healthy volunteers (n = 5), were injected with HP [1-13C]pyruvate dissolved in D2O and imaged with a metabolite-specific 3D dual-echo dynamic EPI sequence at 3T at one site (Site 1). Volunteers were monitored following the procedure to assess safety. Image characteristics, including SNR, were compared to data acquired in a separate cohort using water as a solvent (n = 5) at another site (Site 2). The apparent spin-lattice relaxation time (T1) of [1-13C]pyruvate was determined both in vitro and in vivo from a mono-exponential fit to the image intensity at each time point of our dynamic data. RESULTS: All volunteers completed the study safely and reported no adverse effects. The use of D2O increased the T1 of [1-13C]pyruvate from 66.5 ± 1.6 s to 92.1 ± 5.1 s in vitro, which resulted in an increase in signal by a factor of 1.46 ± 0.03 at the time of injection (90 s after dissolution). The use of D2O also increased the apparent relaxation time of [1-13C]pyruvate by a factor of 1.4 ± 0.2 in vivo. After adjusting for inter-site SNR differences, the use of D2O was shown to increase image SNR by a factor of 2.6 ± 0.2 in humans. CONCLUSIONS: HP [1-13C]pyruvate in D2O is safe for human imaging and provides an increase in T1 and SNR that may improve image quality.

CD38-targeted Immuno-PET of Multiple Myeloma: From Xenograft Models to First-in-Human Imaging.

Background Current measurements of multiple myeloma disease burden are suboptimal. Daratumumab is a monoclonal antibody that targets CD38, an antigen expressed on nearly all myeloma cells. Purpose To demonstrate preclinical and first-in-human application of an antibody composed of the native daratumumab labeled with the positron-emitting radionuclide zirconium 89 (89Zr) through the chelator deferoxamine (DFO), or 89Zr-DFO-daratumumab, for immunologic PET imaging of multiple myeloma. Materials and Methods 89Zr-DFO-daratumumab was synthesized by conjugating 89Zr to daratumumab with DFO. A murine xenograft model using CD38-positive OPM2 multiple myeloma cells was used to evaluate CD38-specificity of 89Zr-DFO-daratumumab. Following successful preclinical imaging, a prospective phase I study of 10 patients with multiple myeloma was performed. Study participants received 74 MBq (2 mCi) of intravenous 89Zr-DFO-daratumumab. Each participant underwent four PET/CT scans over the next 8 days, as well as blood chemistry and whole-body counts, to determine safety, tracer biodistribution, pharmacokinetics, and radiation dosimetry. Because 89Zr has a half-life of 78 hours, only a single administration of tracer was needed to obtain all four PET/CT scans. Results 89Zr-DFO-daratumumab was synthesized with radiochemical purity greater than 99%. In the murine model, substantial bone marrow uptake was seen in OPM2 mice but not in healthy mice, consistent with CD38-targeted imaging of OPM2 multiple myeloma cells. In humans, 89Zr-DFO-daratumumab was safe and demonstrated acceptable dosimetry. 89Zr-DFO-daratumumab uptake was visualized at PET in sites of osseous myeloma. Conclusion These data demonstrate successful CD38-targeted immunologic PET imaging of multiple myeloma in a murine model and in humans. © RSNA, 2020 Online supplemental material is available for this article.

Identification of HER2-Positive Metastases in Patients with HER2-Negative Primary Breast Cancer by Using HER2-targeted 89Zr-Pertuzumab PET/CT.

Background Human epidermal growth factor receptor 2 (HER2)-targeted therapies are successful in patients with HER2-positive malignancies; however, spatial and temporal heterogeneity of HER2 expression may prevent identification of optimal patients for these therapies. Purpose To determine whether imaging with the HER2-targeted PET tracer zirconium 89 (89Zr)-pertuzumab can depict HER2-positive metastases in women with HER2-negative primary breast cancer. Materials and Methods From January to June 2019, women with biopsy-proven HER2-negative primary breast cancer and biopsy-proven metastatic disease were enrolled in a prospective clinical trial (ClinicalTrials.gov NCT02286843) and underwent 89Zr-pertuzumab PET/CT for noninvasive whole-biopsy evaluation of potential HER2-positive metastases. 89Zr-pertuzumab-avid foci that were suspicious for HER2-positive metastases were tissue sampled and examined by pathologic analysis to document HER2 status. Results Twenty-four women (mean age, 55 years ± 11 [standard deviation]) with HER2-negative primary breast cancer were enrolled. Six women demonstrated foci at 89Zr-pertuzumab PET/CT that were suspicious for HER2-positive disease. Of these six women, three had biopsy-proven HER2-positive metastases, two had pathologic findings that demonstrated HER2-negative disease, and one had a fine-needle aspirate with inconclusive results. Conclusion Human epidermal growth factor receptor 2 (HER2)-targeted imaging with zirconium 89-pertuzumab PET/CT was successful in detecting HER2-positive metastases in women with HER2-negative primary breast cancer. This demonstrates the ability of targeted imaging to identify patients for targeted therapies that might not otherwise be considered. © RSNA, 2020 Online supplemental material is available for this article. See the editorial by Mankoff and Pantel in this issue.

Comparison of 68Ga-DOTA-JR11 PET/CT with dosimetric 177Lu-satoreotide tetraxetan (177Lu-DOTA-JR11) SPECT/CT in patients with metastatic neuroendocrine tumors undergoing peptide receptor radionuclide therapy.

PURPOSE: Paired imaging/therapy with radiolabeled somatostatin receptor (SSTR) antagonists is a novel approach in neuroendocrine tumors (NETs). The aim of this study was to compare tumor uptake of 68Ga-DOTA-JR11 and 177Lu-satoreotide tetraxetan (177Lu-DOTA-JR11) in patients with NETs. METHODS: As part of a prospective clinical trial, 20 patients with metastatic NETs underwent 68Ga-DOTA-JR11 PET/CT and serial imaging with 177Lu-satoreotide tetraxetan. PET/CT and SPECT/CT parameters for lesion uptake and absorbed dose of 177Lu-satoreotide tetraxetan in lesions were compared using linear regression analysis and Pearson correlation. RESULTS: A total of 95 lesions were analyzed on 68Ga-DOTA-JR11 PET/CT and 177Lu-satoreotide tetraxetan SPECT/CT. SUVs and tumor-to-normal-tissue ratios on PET/CT and SPECT/CT were significantly correlated (p < 0.01), but the degree of correlation was modest with Pearson correlation coefficients ranging from 0.3 to 0.7. Variation in intrapatient lesional correlation was observed. Nevertheless, in all patients, the lesion SUVpeak uptake ratio for 177Lu-satoreotide tetraxetan vs. 68Ga-DOTA-JR11 was high; even in those with low uptake on 68Ga-DOTA-JR11 PET/CT (SUVpeak ≤ 10), a ratio of 8.0 ± 5.2 was noted. Correlation of SUVpeak of 68Ga-DOTA-JR11 with projected 177Lu-satoreotide tetratexan-absorbed dose (n = 42) was modest (r = 0.5, p < 0.01), while excellent correlation of SUVpeak of 177Lu-satoreotide tetraxetan with projected 177Lu-satoreotide tetraxetan-absorbed dose was noted (r = 0.9, p < 0.0001). CONCLUSION: Our study shows that 68Ga-DOTA-JR11 PET can be used for patient selection and PRRT and that low tumor uptake on PET should not preclude patients from treatment with 177Lu-satoreotide tetraxetan. The ability to use single time-point SPECT/CT for absorbed dose calculations could facilitate dosimetry regimens, save costs, and improve patient convenience.

Biodistribution and radiation dose estimates for 68Ga-DOTA-JR11 in patients with metastatic neuroendocrine tumors.

PURPOSE: Somatostatin receptor antagonists have shown promise for imaging neuroendocrine tumors (NETs) in preclinical studies, but clinical data is still very limited. In this study, we assess the feasibility of using the novel somatostatin antagonist 68Ga-DOTA-JR11 for PET imaging of NETs. METHODS: Twenty patients with advanced NETs underwent whole-body PET/CT imaging 60 min after injection of 169 MBq (median) 68Ga-DOTA-JR11 as part of a prospective study. Volumes of interest were drawn around up to four 68Ga-DOTA-JR11-avid lesions per patient (with uptake greater than liver) and standardized uptake values were estimated. Additionally, target-to-normal tissue ratios were calculated. A subset of six patients had additional imaging (25-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney, and a whole-body PET/CT scan at 30 min post-injection) to determine the time course of tracer distribution and facilitate radiation dose estimates. Absorbed doses were calculated using OLINDA/EXM 1.0. RESULTS: In contrast to the known biodistribution of somatostatin receptor agonists, little or no uptake above background was seen in the pituitary gland, spleen, adrenals, and uninvolved liver; e.g., median spleen SUVmean 1.4 (range: 0.7-1.8), liver SUVmean 1.1 (0.7-1.9). A total of 42 tumor lesions were analyzed with median SUVmax 13.0 (range: 2.9-94), TNR blood 9.3 (1.8-87), TNR spleen 4.9 (1.9-48), TNR kidney 2.2 (0.52-28), and TNR liver 10.5 (2.3-107). Tumor uptake reached plateau levels by 20-30 min post-injection. The highest absorbed dose estimates (mGy/MBq) to normal tissues were: urinary bladder wall (0.30; SD 0.06) and kidneys (0.050; SD 0.013). The effective dose (ICRP 103) was 0.022 (SD 0.003) mSv/MBq. CONCLUSIONS: 68Ga-DOTA-JR11 demonstrated rapid tumor uptake, high tumor/background ratios, and rapid clearance from blood. The low liver background is advantageous and may facilitate detection of liver metastases. Dosimetric data compare favorably with published data for 68Ga-DOTATATE and 68Ga-DOTATOC.

Pharmacokinetics and Biodistribution of a [89Zr]Zr-DFO-MSTP2109A Anti-STEAP1 Antibody in Metastatic Castration-Resistant Prostate Cancer Patients.

A six-transmembrane epithelial antigen of prostate-1 (STEAP1) is a newly identified target in prostate cancer. The use of radio-labeled STEAP1-targeting antibodies with positron emission tomography (PET) may allow for detection of sites of metastatic prostate cancer and may refine patient selection for antigen-directed therapies. This was a prospective study in seven patients with metastatic castration-resistant prostate cancer who had at least one archival biopsy that was STEAP1-positive by immunohistochemistry. Patients received intravenous injections of ∼185 MBq and 10 mg of [89Zr]Zr-DFO-MSTP2109A, a humanized IgG1 monoclonal antibody directed against STEAP1. PET/CT images, blood samples, and whole-body counts were monitored longitudinally in six patients. Here, we report on safety, biodistribution, pharmacokinetics, dose estimates to normal tissues, and initial tumor targeting for this group of patients. There was no significant acute or subacute toxicity. Favorable biodistribution and enhanced lesion uptake (in both bone and soft tissue) were observed on imaging using a mass of 10 mg of DFO-MSTP2109A. The best lesion discrimination was seen at the latest imaging time, a median of 6 days postadministration. Pharmacokinetics showed a median serum T1/2 ß of 198 h, volume of central compartment of 3.54 L (similar to plasma volume), and clearance of 19.7 mL/h. The median biologic T1/2 for whole-body retention was 469 h. The highest mean absorbed doses to normal organs (mGy/MBq) were 1.18, 1.11, 0.78, 0.73, and 0.71 for liver, heart wall, lung, kidney, and spleen, respectively. Excellent targeting of metastatic prostate sites in both bone and soft tissue was observed, with an optimal imaging time of 6 days postadministration. The liver and heart were the normal organs that experienced the highest absorbed doses. The pharmacokinetics were similar to other antibodies without major cross-reactivity with normal tissues. A more detailed analysis of lesion targeting in a larger patient population with correlation to immunohistology and standard imaging modalities has been reported.

Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-centre, dose-escalation, phase 1 trial.

BACKGROUND: Diffuse intrinsic pontine glioma is one of the deadliest central nervous system tumours of childhood, with a median overall survival of less than 12 months. Convection-enhanced delivery has been proposed as a means to efficiently deliver therapeutic agents directly into the brainstem while minimising systemic exposure and associated toxic effects. We did this study to evaluate the safety of convection-enhanced delivery of a radioimmunotherapy agent targeting the glioma-associated B7-H3 antigen in children with diffuse intrinsic pontine glioma. METHODS: We did a phase 1, single-arm, single-centre, dose-escalation study at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients were aged 3-21 years and had diffuse intrinsic pontine glioma as diagnosed by consensus of a multidisciplinary paediatric neuro-oncology team; a Lansky (patients <16 years of age) or Karnofsky (patients ≥16 years) performance score of at least 50 at study entry; a minimum weight of 8 kg; and had completed external beam radiation therapy (54·0-59·4 Gy at 1·8 Gy per fraction over 30-33 fractions) at least 4 weeks but no more than 14 weeks before enrolment. Seven dose-escalation cohorts were planned based on standard 3 + 3 rules: patients received a single infusion of 9·25, 18·5, 27·75, 37, 92·5, 120·25, or 148 MBq, respectively, at a concentration of about 37 MBq/mL by convection-enhanced delivery of the radiolabelled antibody [124I]-8H9. The primary endpoint was identification of the maximum tolerated dose. The analysis of the primary endpoint was done in the per-protocol population (patients who received the full planned dose of treatment), and all patients who received any dose of study treatment were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01502917, and is ongoing with an expanded cohort. FINDINGS: From April 5, 2012, to Oct 8, 2016, 28 children were enrolled and treated in the trial, of whom 25 were evaluable for the primary endpoint. The maximum tolerated dose was not reached as no dose-limiting toxicities were observed. One (4%) of 28 patients had treatment-related transient grade 3 hemiparesis and one (4%) had grade 3 skin infection. No treatment-related grade 4 adverse events or deaths occurred. Estimated volumes of distribution (Vd) were linearly dependent on volumes of infusion (Vi) and ranged from 1·5 to 20·1 cm3, with a mean Vd/Vi ratio of 3·4 (SD 1·2). The mean lesion absorbed dose was 0·39 Gy/MBq 124I (SD 0·20). Systemic exposure was negligible, with an average lesion-to-whole body ratio of radiation absorbed dose higher than 1200. INTERPRETATION: Convection-enhanced delivery in the brainstem of children with diffuse intrinsic pontine glioma who have previously received radiation therapy seems to be a rational and safe therapeutic strategy. PET-based dosimetry of the radiolabelled antibody [124I]-8H9 validated the principle of using convection-enhanced delivery in the brain to achieve high intra-lesional dosing with negligible systemic exposure. This therapeutic strategy warrants further development for children with diffuse intrinsic pontine glioma. FUNDING: National Institutes of Health, The Dana Foundation, The Cure Starts Now, Solving Kids' Cancer, The Lyla Nsouli Foundation, Cookies for Kids' Cancer, The Cristian Rivera Foundation, Battle for a Cure, Cole Foundation, Meryl & Charles Witmer Charitable Foundation, Tuesdays with Mitch Charitable Foundation, and Memorial Sloan Kettering Cancer Center.

In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R)-4-Fluoroglutamine.

Purpose To assess the clinical safety, pharmacokinetics, and tumor imaging characteristics of fluorine 18-(2S,4R)-4-fluoroglutamine (FGln), a glutamine analog radiologic imaging agent. Materials and Methods This study was approved by the institutional review board and conducted under a U.S. Food and Drug Administration-approved Investigational New Drug application in accordance with the Helsinki Declaration and the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Between January 2013 and October 2016, 25 adult patients with cancer received an intravenous bolus of FGln tracer (mean, 244 MBq ± 118, <100 µg) followed by positron emission tomography (PET) and blood radioassays. Patient data were summarized with descriptive statistics. FGln biodistribution and plasma amino acid levels in nonfasting patients (n = 13) were compared with those from patients who fasted at least 8 hours before injection (n = 12) by using nonparametric one-way analysis of variance with Bonferroni correction. Tumor FGln avidity versus fluorodeoxyglucose (FDG) avidity in patients with paired PET scans (n = 15) was evaluated with the Fisher exact test. P < .05 was considered indicative of a statistically significant difference. Results FGln PET depicted tumors of different cancer types (breast, pancreas, renal, neuroendocrine, lung, colon, lymphoma, bile duct, or glioma) in 17 of the 25 patients, predominantly clinically aggressive tumors with genetic mutations implicated in abnormal glutamine metabolism. Acute fasting had no significant effect on FGln biodistribution and plasma amino acid levels. FGln-avid tumors were uniformly FDG-avid but not vice versa (P = .07). Patients experienced no adverse effects. Conclusion Preliminary human FGln PET trial results provide clinical validation of abnormal glutamine metabolism as a potential tumor biomarker for targeted radiotracer imaging in several different cancer types. © RSNA, 2018 Online supplemental material is available for this article. Clinical trial registration no. NCT01697930.

A phase II study of radioimmunotherapy with intraventricular 131 I-3F8 for medulloblastoma.

BACKGROUND: High-risk and recurrent medulloblastoma (MB) is associated with significant mortality. The murine monoclonal antibody 3F8 targets the cell-surface disialoganglioside GD2 on MB. We tested the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy (cRIT) with intraventricular 131 I-labeled 3F8 in patients with MB on a phase II clinical trial. METHODS: Patients with histopathologically confirmed high-risk or recurrent MB were eligible for cRIT. After determining adequate cerebrospinal fluid (CSF) flow, patients received 2 mCi (where Ci is Curie) 124 I-3F8 or 131 I-3F8 with nuclear imaging for dosimetry, followed by up to four therapeutic (10 mCi/dose) 131 I-3F8 injections. Dosimetry estimates were based on serial CSF and blood samplings over 48 hr plus region-of-interest analyses on serial imaging scans. Disease evaluation included pre- and posttherapy brain/spine magnetic resonance imaging approximately every 3 months for the first year after treatment, and every 6-12 months thereafter. RESULTS: Forty-three patients received a total of 167 injections; 42 patients were evaluable for outcome. No treatment-related deaths occurred. Toxicities related to drug administration included acute bradycardia with somnolence, headache, fatigue, and CSF pleocytosis consistent with chemical meningitis and dystonic reaction. Total CSF absorbed dose was 1,453 cGy (where Gy is Gray; 350.0-2,784). Median overall survival from first dose of cRIT was 24.9 months (95% confidence interval [CI]:16.3-55.8). Patients treated in radiographic and cytologic remission were at a lower risk of death compared to patients with radiographically measurable disease (hazard ratio: 0.40, 95% CI: 0.18-0.88, P = 0.024). CONCLUSIONS: cRIT with 131 I-3F8 is safe, has favorable dosimetry to CSF, and when added to salvage therapy using conventional modalities, may have clinical utility in maintaining remission in high-risk or recurrent MB.

A prospective pilot study of (89)Zr-J591/prostate specific membrane antigen positron emission tomography in men with localized prostate cancer undergoing radical prostatectomy.

PURPOSE: In this pilot study we explored the feasibility of (89)Zr labeled J591 monoclonal antibody positron emission tomography of localized prostate cancer. MATERIALS AND METHODS: Before scheduled radical prostatectomy 11 patients were injected intravenously with (89)Zr-J591, followed 6 days later by whole body positron emission tomography. Patients underwent surgery the day after imaging. Specimens were imaged by ex vivo micro positron emission tomography and a custom 3 Tesla magnetic resonance scanner coil. Positron emission tomography images and histopathology were correlated. RESULTS: Median patient age was 61 years (range 47 to 68), median prostate specific antigen was 5.2 ng/ml (range 3.5 to 12.0) and median biopsy Gleason score of the 11 index lesions was 7 (range 7 to 9). On histopathology 22 lesions were identified. Median lesion size was 5.5 mm (range 2 to 21) and median Gleason score after radical prostatectomy was 7 (range 6 to 9). Eight of 11 index lesions (72.7%) were identified by in vivo positron emission tomography. Lesion identification improved with increasing lesion size for in vivo and ex vivo positron emission tomography (each p <0.0001), and increasing Gleason score (p = 0.14 and 0.01, respectively). Standardized uptake values appeared to correlate with increased Gleason score but not significantly (p = 0.19). CONCLUSIONS: To our knowledge this is the first report of (89)Zr-J591/prostate specific membrane antigen positron emission tomography in localized prostate cancer cases. In this setting (89)Zr-J591 bound to tumor foci in situ and positron emission tomography identified primarily Gleason score 7 or greater and larger tumors, likely corresponding to clinically significant disease warranting definitive therapy. A future, larger clinical validation trial is planned to better define the usefulness of (89)Zr-J591 positron emission tomography for localized prostate cancer.

89Zr-huJ591 immuno-PET imaging in patients with advanced metastatic prostate cancer.

PURPOSE: Given the bone tropism of prostate cancer, conventional imaging modalities poorly identify or quantify metastatic disease. (89)Zr-huJ591 positron emission tomography (PET) imaging was performed in patients with metastatic prostate cancer to analyze and validate this as an imaging biomarker for metastatic disease. The purpose of this initial study was to assess safety, biodistribution, normal organ dosimetry, and optimal imaging time post-injection for lesion detection. METHODS: Ten patients with metastatic prostate cancer received 5 mCi of (89)Zr-huJ591. Four whole-body scans with multiple whole-body count rate measurements and serum activity concentration measurements were obtained in all patients. Biodistribution, clearance, and lesion uptake by (89)Zr-huJ591 immuno-PET imaging was analyzed and dosimetry was estimated using MIRD techniques. Initial assessment of lesion targeting of (89)Zr-huJ591 was done. Optimal time for imaging post-injection was determined. RESULTS: The dose was well tolerated with mild chills and rigors seen in two patients. The clearance of (89)Zr-huJ591 from serum was bi-exponential with biological half-lives of 7 ± 4.5 h (range 1.1-14 h) and 62 ± 13 h (range 51-89 h) for initial rapid and later slow phase. Whole-body biological clearance was 219 ± 48 h (range 153-317 h). The mean whole-body and liver residence time was 78.7 and 25.6 h, respectively. Dosimetric estimates to critical organs included liver 7.7 ± 1.5 cGy/mCi, renal cortex 3.5 ± 0.4 cGy/mCi, and bone marrow 1.2 ± 0.2 cGy/mCi. Optimal time for patient imaging after injection was 7 ± 1 days. Lesion targeting of bone or soft tissue was seen in all patients. Biopsies were performed in 8 patients for a total 12 lesions, all of which were histologically confirmed as metastatic prostate cancer. One biopsy-proven lesion was not positive on (89)Zr-huJ591, while the remaining 11 lesions were (89)Zr-huJ591 positive. Two biopsy-positive nodal lesions were noted only on (89)Zr-huJ591 study, while the conventional imaging modality was negative. CONCLUSION: (89)Zr-huJ591 PET imaging of prostate-specific membrane antigen expression is safe and shows good localization of disease in prostate cancer patients. Liver is the critical organ for dosimetry, and 7 ± 1 days is the optimal imaging time. A larger study is underway to determine lesion detection in an expanded cohort of patients with metastatic prostate cancer.

Methods for the Production of Radiolabeled Bioagents for ImmunoPET.

Immunoglobulin-based positron emission tomography (ImmunoPET) is making increasingly significant contributions to the nuclear imaging toolbox. The exquisite specificity of antibodies combined with the high-resolution imaging of PET enables clinicians and researchers to localize diseases, especially cancer, with a high degree of spatial certainty. This review focuses on the radiopharmaceutical preparation necessary to obtain those images-the work behind the scenes, which occurs even before the patient or animal is injected with the radioimmunoconjugate. The focus of this methods review will be the chelation of four radioisotopes to their most common and clinically relevant chelators.

Nuclear-Based Labeling of Cellular Immunotherapies: A Simple Protocol for Preclinical Use.

Labeling and tracking existing and emerging cell-based immunotherapies using nuclear imaging is widely used to guide the preclinical phases of development and testing of existing and new emerging off-the-shelf cell-based immunotherapies. In fact, advancing our knowledge about their mechanism of action and limitations could provide preclinical support and justification for moving towards clinical experimentation of newly generated products and expedite their approval by the Food and Drug Administration (FDA).Here we provide the reader with a ready to use protocol describing the labeling methodologies and practical procedures to render different candidate cell therapies in vivo traceable by nuclear-based imaging. The protocol includes sufficient practical details to aid researchers at all career stages and from different fields in familiarizing with the described concepts and incorporating them into their work.

Good practices for 89Zr radiopharmaceutical production and quality control.

BACKGROUND: During the previous two decades, PET imaging of biopharmaceuticals radiolabeled with zirconium-89 has become a consistent tool in preclinical and clinical drug development and patient selection, primarily due to its advantageous physical properties that allow straightforward radiolabeling of antibodies (89Zr-immuno-PET). The extended half-life of 78.4 h permits flexibility with respect to the logistics of tracer production, transportation, and imaging and allows imaging at later points in time. Additionally, its relatively low positron energy contributes to high-sensitivity, high-resolution PET imaging. Considering the growing interest in radiolabeling antibodies, antibody derivatives, and other compound classes with 89Zr in both clinical and pre-clinical settings, there is an urgent need to acquire valuable recommendations and guidelines towards standardization of labeling procedures. MAIN BODY: This review provides an overview of the key aspects of 89Zr-radiochemistry and radiopharmaceuticals. Production of 89Zr, conjugation with the mostly used chelators and radiolabeling strategies, and quality control of the radiolabeled products are described in detail, together with discussions about alternative options and critical steps, as well as recommendations for troubleshooting. Moreover, some historical background on 89Zr-immuno-PET, coordination chemistry of 89Zr, and future perspectives are provided. This review aims to serve as a quick-start guide for scientists new to the field of 89Zr-immuno-PET and to suggest approaches for harmonization and standardization of current procedures. CONCLUSION: The favorable PET imaging characteristics of 89Zr, its excellent availability due to relatively simple production and purification processes, and the development of suitable bifunctional chelators have led to the widespread use of 89Zr. The combination of antibodies and 89Zr, known as 89Zr-immuno-PET, has become a cornerstone in drug development and patient selection in recent years. Despite the advanced state of 89Zr-immuno-PET, new developments in chelator conjugation and radiolabeling procedures, application in novel compound classes, and improved PET scanner technology and quantification methods continue to reshape its landscape towards improving clinical outcomes.

[89Zr]ZrCl4 for direct radiolabeling of DOTA-based precursors.

INTRODUCTION: Zirconium-89 (89Zr) is a positron emitter with several advantages over other shorter-lived positron emission tomography (PET) compatible radiometals such as gallium-68 or copper-64. These include practically unlimited availability, extremely low cost, greatly facilitated distribution logistics, positron energy fit for medical PET imaging, and sufficiently long physical half-life to enable PET imaging at later time points for patient-specific dosimetry estimations. Despite these apparent benefits, the reception of 89Zr in the nuclear medicine community has been tepid. The driving factor for the absence of broader adaptation is mostly routed in its final formulation - [89Zr]zirconium oxalate. While serving as a suitable precursor solution for the gold standard chelator deferoxamine (DFO), [89Zr]Zr-oxalate is inaccessible for the most commonly used chelators, such as the macrocyclic DOTA, due to its pre-chelated state. Consequently, pioneering work has been conducted by multiple research groups to create oxalate-free forms of [89Zr]Zr4+, either via chemical conversion of oxalate into other counterion forms or via direct radiochemical isolation of [89Zr]ZrCl4, showing that [89Zr]Zr-DOTA complexes are possible and stable. However, this success was accompanied by challenges, including complex and labor-intensive radiochemical processing and radiolabeling procedures as well as the relatively minuscule conversion rates. Here, we report on the direct production of [89Zr]ZrCl4 avoiding oxalate and metal contaminants to enable efficient radiolabeling of DOTA constructs. METHODS: We based our direct production of [89Zr]ZrCl4 on previously reported methods and further optimized its quality by including an additional iron-removing step using the TK400 Resin. Here, we avoided using oxalic acid and effectively minimized the content of trace metal contaminants. Our two-step purification procedure was automated, and we confirmed excellent radionuclide purity, minimal trace metals content, great reactivity over time, and high specific molar activity. In addition, DOTA-based PSMA-617 and DOTAGA-based PSMA-I&T were radiolabeled to demonstrate the feasibility of direct radiolabeling and to estimate the maximum apparent specific activities. Lastly, the biodistribution of [89Zr]Zr-PSMA-617 was assessed in mice bearing PC3-PIP xenografts, and the results were compared to the previously published data. RESULTS: A total of 18 batches, ranging from 6.9 to 20 GBq (186 to 541 mCi), were produced. The specific molar activity for [89Zr]ZrCl4 exceeded 0.96 GBq (26 mCi) per nanomole of zirconium. The radionuclidic purity was >99 %, and the trace metals content was in the <1 ppm range. The [89Zr]ZrCl4 remained in its reactive chemical form for at least five days when stored in cyclic olefin polymer (COP) vials. Batches of 11.1 GBq (300 mCi) of [89Zr]Zr-PSMA-617 and 14.4 GBq (390 mCi) of [89Zr]Zr-PSMA-I&T, corresponding to specific activities of 11.1 MBq/µg (0.3 mCi/µg), and 14.4 MBq/µg (0.39 mCi/µg), respectively, were produced. [89Zr]Zr-PSMA-617 animal PET imaging results were in agreement with the previously published data. CONCLUSION: In this work, we report on a suitable application of TK400 Resin to remove iron during [89Zr]ZrCl4 radiochemical isolation. The breakthrough allows for direct radiolabeling of DOTA-based constructs with [89Zr]ZrCl4, leading to high apparent molar activities and excellent conversion rates.

Theranostic Intratumoral Convection-Enhanced Delivery of 124I-Omburtamab in Patients with Diffuse Intrinsic Pontine Glioma: Pharmacokinetics and Lesion Dosimetry.

Diffuse intrinsic pontine glioma (DIPG) is a rare childhood malignancy with poor prognosis. There are no effective treatment options other than external beam therapy. We conducted a pilot, first-in-human study using 124I-omburtamab imaging and theranostics as a therapeutic approach using a localized convection-enhanced delivery (CED) technique for administering radiolabeled antibody. We report the detailed pharmacokinetics and dosimetry results of intratumoral delivery of 124I-omburtamab. Methods: Forty-five DIPG patients who received 9.0-370.7 MBq of 124I-omburtamab intratumorally via CED underwent serial brain and whole-body PET/CT imaging at 3-5 time points after injection within 4, 24-48, 72-96, 120-144, and 168-240 h from the end of infusion. Serial blood samples were obtained for kinetic analysis. Whole-body, blood, lesion, and normal-tissue activities were measured, kinetic parameters (uptake and clearance half-life times) estimated, and radiation-absorbed doses calculated using the OLINDA software program. Results: All patients showed prominent activity within the lesion that was retained over several days and was detectable up to the last time point of imaging, with a mean 124I residence time in the lesion of 24.9 h and dose equivalent of 353 ± 181 mSv/MBq. Whole-body doses were low, with a dose equivalent of 0.69 ± 0.28 mSv/MBq. Systemic distribution and activities in normal organs and blood were low. Radiation dose to blood was very low, with a mean value of 0.27 ± 0.21 mGy/MBq. Whole-body clearance was monoexponential with a mean biologic half-life of 62.7 h and an effective half-life of 37.9 h. Blood clearance was biexponential, with a mean biologic half-life of 22.2 h for the rapid α phase and 155 h for the slower ß phase. Conclusion: Intratumoral CED of 124I-omburtamab is a novel theranostics approach in DIPG. It allows for delivery of high radiation doses to the DIPG lesions, with high lesion activities and low systemic activities and high tumor-to-normal-tissue ratios and achieving a wide safety margin. Imaging of the actual therapeutic administration of 124I-omburtamab allows for direct estimation of the therapeutic lesion and normal-tissue-absorbed doses.

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.