Radiolabeled Somatostatin Receptor Antagonist Versus Agonist for Peptide Receptor Radionuclide Therapy in Patients with Therapy-Resistant Meningioma: PROMENADE Phase 0 Study.

Our primary aim was to compare the therapeutic index (tumor-to-bone marrow and tumor-to-kidney absorbed-dose ratios) of the new radiolabeled somatostatin receptor antagonist [177Lu]Lu-DOTA-JR11 with the established radiolabeled somatostatin receptor agonist [177Lu]Lu-DOTATOC in the same patients with progressive, standard therapy-refractory meningioma. Methods: In this prospective, single-center, open-label phase 0 study (NCT04997317), 6 consecutive patients were included: 3 men and 3 women (mean age, 63.5 y). Patients received 6.9-7.3 GBq (standard injected radioactivity) of [177Lu]Lu-DOTATOC followed by 3.3-4.9 GBq (2 GBq/m2 × body surface area) of [177Lu]Lu-DOTA-JR11 at an interval of 10 ± 1 wk. In total, 1 [177Lu]Lu-DOTATOC and 2-3 [177Lu]Lu-DOTA-JR11 treatment cycles were performed. Quantitative SPECT/CT was done at approximately 24, 48, and 168 h after injection of both radiopharmaceuticals to calculate meningioma and organ absorbed doses as well as tumor-to-organ absorbed-dose ratios (3-dimensional segmentation approach for meningioma, kidneys, liver, bone marrow, and spleen). Results: The median of the meningioma absorbed dose of 1 treatment cycle was 3.4 Gy (range, 0.8-10.2 Gy) for [177Lu]Lu-DOTATOC and 11.5 Gy (range, 4.7-22.7 Gy) for [177Lu]Lu-DOTA-JR11. The median bone marrow and kidney absorbed doses after 1 treatment cycle were 0.11 Gy (range, 0.05-0.17 Gy) and 2.7 Gy (range, 1.3-5.3 Gy) for [177Lu]Lu-DOTATOC and 0.29 Gy (range, 0.16-0.39 Gy) and 3.3 Gy (range, 1.6-5.9 Gy) for [177Lu]Lu-DOTA-JR11, resulting in a 1.4 (range, 0.9-1.9) times higher median tumor-to-bone marrow absorbed-dose ratio and a 2.9 (range, 2.0-4.8) times higher median tumor-to-kidney absorbed-dose ratio with [177Lu]Lu-DOTA-JR11. According to the Common Terminology Criteria for Adverse Events version 5.0, 2 patients developed reversible grade 2 lymphopenia after 1 cycle of [177Lu]Lu-DOTATOC. Afterward, 2 patients developed reversible grade 3 lymphopenia and 1 patient developed reversible grade 3 lymphopenia and neutropenia after 2-3 cycles of [177Lu]Lu-DOTA-JR11. No grade 4 or 5 adverse events were observed at 15 mo or more after the start of therapy. The disease control rate was 83% (95% CI, 53%-100%) at 12 mo or more after inclusion. Conclusion: Treatment with 1 cycle of [177Lu]Lu-DOTA-JR11 showed 2.2-5.7 times higher meningioma absorbed doses and a favorable therapeutic index compared with [177Lu]Lu-DOTATOC after injection of 1.4-2.1 times lower activities. The first efficacy results demonstrated a high disease control rate with an acceptable safety profile in the standard therapy for refractory meningioma patients. Therefore, larger studies with [177Lu]Lu-DOTA-JR11 are warranted in meningioma patients.

Peptide Receptor Radionuclide Therapy Is Effective for Clinical Control of Symptomatic Metastatic Insulinoma: A Long-Term Retrospective Analysis.

Metastatic insulinoma is a rare malignant neuroendocrine tumor characterized by inappropriate insulin secretion, resulting in life-threatening hypoglycemia, which is often difficult to treat. There is currently very limited information about the efficacy of peptide receptor radionuclide therapy (PRRT) for clinical control of hypoglycemia. The aim of this long-term retrospective study was to evaluate the therapeutic efficacy of PRRT for improving hypoglycemia, to evaluate the change of medication after PRRT, and to calculate progression-free survival (PFS) and overall survival (OS). Methods: Inclusion criteria were histologically proven somatostatin receptor-positive metastatic malignant insulinoma and at least 2 cycles of [90Y]Y-DOTATOC or [177Lu]Lu-DOTATOC therapy from early 2000 to early 2022. A semiquantitative scoring system was used to quantify the severity and frequency of hypoglycemic episodes under background antihypoglycemic therapy (somatostatin analog, diazoxide, everolimus, corticosteroids): score 0, no hypoglycemic episodes; score 1, hypoglycemic events requiring additional conservative treatment with optimization of nutrition; score 2, severe hypoglycemia necessitating hospitalization and combined medication or history of hypoglycemic coma. Hypoglycemic score before and after PRRT was analyzed. Time of benefit was defined as a time range of fewer hypoglycemic episodes in the observation period than at baseline. Information on antihypoglycemic medication before and after therapy, PFS, and OS was recorded. Results: Twenty-six of 32 patients with a total of 106 [90Y]Y-DOTATOC/[177Lu]Lu-DOTATOC cycles were included. The average observation period was 21.5 mo (range, 2.3-107.4 mo). Before therapy, 81% (n = 21) of the patients had a hypoglycemia score of 2 and 19% (n = 5) had a score of 1. After PRRT, 81% of patients (n = 21) had a decreased score, and the remaining 5 patients showed a stable situation. There was temporary worsening of hypoglycemia just after injection of [90Y]Y-DOTATOC/[177Lu]Lu-DOTATOC in 19% of patients. The average time of benefit in the observation period was 17.2 mo (range, 0-70.2 mo). Antihypoglycemic medication reduction was achieved in 58% (n = 15) of patients. The median OS and PFS after the start of PRRT were 19.7 mo (95% CI, 6.5-32.9 mo) and 11.7 mo (95% CI, 4.9-18.5 mo), respectively. Conclusion: To our knowledge, our study included the largest cohort of patients with malignant insulinoma to be evaluated. Long-lasting symptom control and reduction of antihypoglycemic medications were shown in most patients after late-line PRRT.

Early response monitoring during [177Lu]Lu-PSMA I&T therapy with quantitated SPECT/CT predicts overall survival of mCRPC patients: subgroup analysis of a Swiss-wide prospective registry study.

PURPOSE: To assess early tumor response with quantitated SPECT/CT and to correlate it with clinical outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with 177Lutetium-PSMA I&T therapy. METHODS: Single-center, observational study, part of the prospective Swiss national cancer registry study investigating the safety and efficacy of [177Lu]Lu-PSMA I&T (EKNZ: 2021-01271) in mCRPC patients treated with at least two cycles of [177Lu]Lu-PSMA I&T 6-weekly. After the first and second cycle quantitated SPECT/CT (Symbia Intevo, Siemens) was acquired 48 h after injection (three fields of view from head to thigh, 5 s/frame) and reconstructed using xQuant® (48i, 1 s, 10-mm Gauss). Image analysis: The PSMA-positive total tumor volumes (TTV) were semi-automatically delineated using a SUV threshold of 3 with MIMencore® (version 7.1.3, Medical Image Merge Software Inc.). Changes in TTV, highest tumor SUVmax, and total tumor SUVmean between cycles 1 and 2 were calculated and grouped into a) stable or decrease and b) increase. Serum PSA levels were assessed at each therapy cycle and at follow-up until progression or death. Changes in TTV, PSA, SUVmax, and SUVmean were correlated with PSA-progression-free survival (PSA-PFS) and the overall survival (OS) using the Kaplan-Meier methodology (log-rank test). RESULTS: Between 07/2020 and 04/2022, 111 patients were screened and 73 finally included in the data analysis. The median follow-up was 8.9 months (range 1.4-26.6 months). Stable or decreased TTV at cycle 2 was associated with longer OS (hazard ratio (HR) 0.28, 95% confidence interval (CI) 0.09-0.86, p < 0.01). Similar, stable, or decreased PSA was associated with longer OS (HR 0.21; CI 0.07-0.62, p < 0.01) and PSA-PFS (HR 0.34; 95% CI 0.16-0.72, p < 0.01). Combining TTV and PSA will result in an augmented prognostic value for OS (HR 0.09; CI 0.01-0.63; p < 0.01) and for PSA-PFS (HR 0.11; CI 0.02-0.68; p < 0.01). A reduction of SUVmax or SUVmean was not prognostically relevant, neither for OS (p 0.88 and 0.7) nor for PSA-PFS (p 0.73 and 0.62, respectively). CONCLUSION: Six weeks after initiating [177Lu]Lu-PSMA I&T, TTV and serum PSA appear to be good prognosticators for OS. Combined together, TTV + PSA change demonstrates augmented prognostic value and can better predict PSA-PFS. Larger studies using TTV change prospectively as an early-response biomarker are warranted for implementing management change towards a more personalized clinical practice.

Improved quality control of [177Lu]Lu-PSMA I&T.

BACKGROUND: Targeted radionuclide therapy with [177Lu]Lu-PSMA I&T (zadavotide guraxetan) has proven high efficacy and safety in treating patients with advanced prostate cancer worldwide. Several methods to determine the radiochemical purity have been reported but also limitations in the HPLC analysis due to retention of the sample and tailing effects when using standard gradients containing trifluoroacetic acid (TFA). We here report on the validation of a method for quality control of [177Lu]Lu-PSMA I&T including determination of radiochemical purity, identity testing and limit test for PSMA I&T by HPLC using a Phosphate buffer /Acetonitrile gradient system, complemented with a TLC system with 0.1N Citrate buffer pH 5 as mobile phase including validation of the methods, batch and stability data as well as identification of the main radiochemical impurity by mass spectrometry. RESULTS: The described HPLC method met the defined acceptance criteria in terms of accuracy, specificity, robustness, linearity, range and LOQ. HPLC analysis revealed symmetrical peaks and quantitative recovery from the column. Batch data showed a radiochemical purity > 95% as determined by HPLC, stability data a pronounced degradation due to radiolysis, which could be limited by addition of ascorbic acid, dilution and storage at low temperatures. The main radiochemical impurity was found to be the de-iodinated form of [177Lu]Lu-PSMA I&T. TLC analysis allowed to determine the amount of free Lu-177 even in the presence of DTPA in the final formulation. CONCLUSION: Overall the described combination of HPLC and TLC provides a reliable tool for quality control of [177Lu]Lu-PSMA I&T.

Safety, Biodistribution, and Radiation Dosimetry of 68Ga-OPS202 in Patients with Gastroenteropancreatic Neuroendocrine Tumors: A Prospective Phase I Imaging Study.

Preclinical and preliminary clinical evidence indicates that radiolabeled somatostatin (sst) receptor antagonists perform better than agonists in detecting neuroendocrine tumors (NETs). We performed a prospective phase I/II study to evaluate the sst receptor antagonist 68Ga-OPS202 (68Ga-NODAGA-JR11; NODAGA = 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid and JR11 = Cpa-c(dCys-Aph(Hor)-dAph(Cbm)-Lys-Thr-Cys)-dTyr-NH2)) for PET imaging. Here, we report the results of phase I of the study. Methods: Patients received 2 single 150-MBq intravenous injections of 68Ga-OPS202 3-4 wk apart (15 µg of peptide at visit 1 and 50 µg at visit 2). At visit 1, a dynamic PET/CT scan over the kidney was obtained during the first 30 min after injection, and static whole-body scans were obtained at 0.5, 1, 2, and 4 h after injection; at visit 2, a static whole-body scan was obtained at 1 h. Blood samples and urine were collected at regular intervals to determine 68Ga-OPS202 pharmacokinetics. Safety, biodistribution, radiation dosimetry, and the most appropriate imaging time point for 68Ga-OPS202 were assessed. Results: Twelve patients with well-differentiated gastroenteropancreatic (GEP) NETs took part in the study. 68Ga-OPS202 cleared rapidly from the blood, with a mean residence time of 2.4 ± 1.1 min/L. The organs with the highest mean dose coefficients were the urinary bladder wall, kidneys, and spleen. The calculated effective dose was 2.4E-02 ± 0.2E-02 mSv/MBq, corresponding to 3.6 mSv, for a reference activity of 150 MBq. Based on total numbers of detected malignant lesions, the optimal time window for the scan was between 1 and 2 h. For malignant liver lesions, the time point at which most patients had the highest mean tumor contrast was 1 h. 68Ga-OPS202 was well tolerated; adverse events were grade 1 or 2, and there were no signals of concern from laboratory blood or urinalysis tests. Conclusion:68Ga-OPS202 showed favorable biodistribution and imaging properties, with optimal tumor contrast between 1 and 2 h after injection. Dosimetry analysis revealed that the dose delivered by 68Ga-OPS202 to organs is similar to that delivered by other 68Ga-labeled sst analogs. Further evaluation of 68Ga-OPS202 for PET/CT imaging of NETs is therefore warranted.

Development of 68Ga- and 89Zr-Labeled Exendin-4 as Potential Radiotracers for the Imaging of Insulinomas by PET.

UNLABELLED: Clinical studies have demonstrated the potential of radiometallated exendin-4 derivatives for the imaging of glucagonlike peptide-1 receptor-overexpressing insulinomas. Recently investigated exendin-4 derivatives were radiolabeled with the SPECT isotopes 99mTc or 111In. Despite promising results, the low spatial resolution associated with SPECT and the occasional need to perform imaging several days after injection for the demarcation of insulinomas from the kidneys represent current limitations. The aim of this work was the development of exendin-4 derivatives for the imaging of insulinomas by high-resolution PET at early or late time points after injection of the radiotracer. METHODS: An exendin-4 derivative conjugated to desferrioxamine (DFO) was used for radiolabeling with the PET isotopes 68Ga and 89Zr. Both radiotracers were evaluated in vitro with RIN-m5F cells for their cell internalization properties as well as affinities and specificities toward the glucagonlike peptide-1 receptor. Serum stabilities of the radiopeptides were assessed in blood serum, and their distribution coefficient was determined by the shake-flask method. Biodistribution experiments were performed with nude mice bearing RIN-m5F xenografts. For all experiments, clinically evaluated [Lys40-(AHX-DTPA-111In)NH2]exendin-4 was used as a reference compound. RESULTS: [Lys40-(AHX-DFO)NH2]exendin-4 was labeled with 89Zr and 68Ga in high radiochemical yield and purity. In vitro experiments showed favorable cell uptake and receptor affinity for [Lys40-(AHX-DFO-68Ga)NH2]exendin-4, and [Lys40-(AHX-DFO-89Zr)NH2]exendin-4 and [Lys40-(AHX-DTPA-111In)NH2]exendin-4 performed similarly well. In biodistribution experiments, [Lys40-(AHX-DFO-68Ga)NH2]exendin-4 exhibited a significantly enhanced tumor uptake 1 h after injection in comparison to the other 2 radiotracers. Tumor uptake of [Lys40-(AHX-DFO-89Zr)NH2]exendin-4 was comparable to that of [Lys40-(AHX-DTPA-111In)NH2]exendin-4 at 1-48 h after injection. All compounds showed a fast blood clearance and low accumulation in receptor-negative organs and tissue with the exception of the kidneys, a known characteristic for exendin-4-based radiotracers. CONCLUSION: 68Ga- and 89Zr-radiolabeled [Lys40-(AHX-DFO)NH2]exendin-4 exhibit characteristics comparable or superior to the clinically tested reference compound [Lys40-(AHX-DTPA-111In)NH2]exendin-4 and, thus, represent potential new tracers for the imaging of insulinomas by PET.

An octadentate bifunctional chelating agent for the development of stable zirconium-89 based molecular imaging probes.

(89)Zr-based imaging agents hold great promise as novel radio-tracers in nuclear medicine. However, insufficient stability of currently used radiometal complexes in vivo is a safety concern for clinical applications. We herein report the first octadentate bifunctional chelating agent for the development of (89)Zr-labelled (bio)conjugates with improved stability.

Expression of different neurokinin-1 receptor (NK1R) isoforms in glioblastoma multiforme: potential implications for targeted therapy.

In clinical trials, overexpression of neurokinin-1 receptors (NK1R) in gliomas has been exploited by intratumoral injection of its radiolabeled ligand, substance P (SP). However, despite proven NK1R expression, patients' response to the therapy was inhomogeneous. This study aims to identify the factors predicting response to NK1R-targeted glioma therapy, thereby allowing the discrimination between potential "responders" and "nonresponders" and thus a personalized therapeutic approach. Four widely used glioblastoma cell lines were examined concerning their RNA levels of full-length and truncated NK1R subtypes. Binding of SP to NK1R and internalization into glioma cells was studied by three different approaches using radiolabeled SP ((177)Lu-[DOTA, Thi(8), Met(O2)(11)]-SP), a fluorescence-labeled SP derivative (SP-FAM), and a toxin-SP conjugate (saporin-SP). While NK1R RNA was detected in all cases, receptor subtype analysis revealed impressive differences between the cell lines; LN319 exhibited the highest level of full-length NK1R RNA. Significant binding of SP conjugates to NK1R, cell internalization, and specific cell killing were only observed with the cell line LN319. Thus, different NK1R subtype profiles of glomerular basement membrane (GBM) cell lines appear to influence the binding of SP conjugates and their cell internalization properties. Both processes are crucial steps for NK1R-based targeted therapy. Pretherapeutic testing for NK1R subtype expression may therefore be advisable before initiation of this generally promising therapeutic modality.

Dual-targeting conjugates designed to improve the efficacy of radiolabeled peptides.

Radiolabeled regulatory peptides are useful tools in nuclear medicine for the diagnosis (imaging) and therapy of cancer. The specificity of the peptides towards GPC receptors, which are overexpressed by cancer cells, and their favorable pharmacokinetic profile make them ideal vectors to transport conjugated radionuclides to tumors and metastases. However, after internalization of the radiopeptide into cancer cells and tumors, a rapid washout of a substantial fraction of the delivered radioactivity is often observed. This phenomenon may represent a limitation of radiopeptides for clinical applications. Here, we report the synthesis, radiolabeling, stability, and in vitro evaluation of a novel, dual-targeting peptide radioconjugate designed to enhance the cellular retention of radioactivity. The described trifunctional conjugate is comprised of a Tc-99m SPECT reporter probe, a cell membrane receptor-specific peptide, and a second targeting entity directed towards mitochondria. While the specificity of the first generation of dual-targeting conjugates towards its extracellular target was demonstrated, intracellular targeting could not be confirmed probably due to non-specific binding or hindered passage through the membrane of the organelle. The work presented describes a novel approach with potential to improve the efficacy of radiopharmaceuticals by enhancing the intracellular retention of radioactivity.

Fluorescent gallium and indium bis(thiosemicarbazonates) and their radiolabelled analogues: synthesis, structures and cellular confocal fluorescence imaging investigations.

New fluorescent and biocompatible aromatic Ga(III)- and In(III)-bis(thiosemicarbazonato) complexes for dual mode optical and PET or SPECT molecular imaging have been synthesised via a synthetic method based on transmetallation reactions from Zn(II) precursors. Complexes have been fully characterised in the solid state by single crystal X-ray diffraction and in solution by spectroscopic methods (UV/Vis, fluorescence, (1)H and (13)C{(1)H} NMR). The bis(thiosemicarbazones) radiolabelled rapidly in high yields under mild conditions with (111)In (a gamma and Auger emitter for SPECT imaging and radiotherapy with t(1/2) = 2.8 d) and (68)Ga (a generator-available positron emitter for PET imaging with t(1/2) = 68 min). Cytotoxicity and biolocalisation studies using confocal fluorescence imaging and fluorescence lifetime imaging (FLIM) techniques have been used to study their in vitro activities and stabilities in HeLa and PC-3 cells to ascertain their suitability as synthetic scaffolds for future multimodality molecular imaging in cancer diagnosis and therapy. The observation that the indium complexes show certain nuclear uptake could be of relevance towards developing (111)In therapeutic agents based on Auger electron emission to induce DNA damage.