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Background: 165Er (t1/2 = 10.4 h, Ex-ray = 47.1 keV (59.4%) and 54.3 keV (14.3%)) is a promising radionuclide suitable for targeted Auger electron therapy of cancer. 165Er can be produced at a relatively low cost, high yield, and high purity using small medical cyclotrons. As a late lanthanide, 165Er is easy to label and can be used as a surrogate for other lanthanides or Ac in proof-of-concept studies. In this report, we explore the radiochemistry, in vitro, and in vivo behavior of [165Er]ErCl3 and [165Er]Er-PSMA-617 to showcase the application of this radionuclide. Particularly, we report the first phantom and preclinical SPECT imaging of this radionuclide leveraging its characteristic X-ray photon emissions. Results: The 165Ho(p,n)165Er nuclear reaction using a 13 MeV cyclotron demonstrated production yields of up to 25 ± 5 MBq. µA−1 h−1 at the end of the bombardment. After the purification (4.0 ± 0.5 h) using a sequential combination of cation exchange and extraction chromatography, 4-h irradiation produced up to 1.5 GBq of [165Er]ErCl3. High molar activity [165Er]Er-PSMA-617 was prepared (~ 200 MBq/nmol). [165Er]Er-PSMA-617 showed a LogD7.4 value of -2.34 ± 0.24 meaning high hydrophilicity of the complex as expected. The stability of [165Er]Er-PSMA-617 in saline, human, and mouse serum was studied and showed intact tracer after 12 h in all three cases. [165Er]ErCl3 and [165Er]Er-PSMA-617 were both taken up by LNCaP cells. PSMA-617 has IC50 at nanomolar range for [165Er]Er-PSMA-617 in LNCaP cells. SPECT images with preclinical phantoms showed good uniformity, spatial resolution, and quantitative accuracy. SPECT/CT imaging in LNCaP tumor-bearing mice injected with [165Er]Er-PSMA-617 showed high tumor uptake and quantitative accuracy when comparing the results to ex vivo biodistribution %IA/g values. Mice injected with [165Er]ErCl3 showed uptake in bone structures and excretion through both liver and kidneys. Conclusions: This study demonstrated the preclinical use of 165Er for the first time. Using [165Er]ErCl3 and [165Er]Er-PSMA-617 as examples, the radiochemistry, cell, and animal studies showed that 165Er can be used as a tool for evaluating targeted radiopharmaceuticals. The X-ray emission from 165Er can be used for quantitative SPECT imaging in mice. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is the most prevalent cancer in elderly men, exhibiting a positive correlation with age. As resistance to treatment has developed, particularly in the progressive stage of the disease and in the presence of microfocal multiple bone metastases, new generation radionuclide therapies have emerged. Recently introduced for treating micrometastatic foci, Terbium-161 ([161Tb]) has shown great promise in prostate cancer treatment. This study investigated the in vitro and in vivo cytotoxicity of Terbium-161 ([161Tb])-radiolabeled prostate-specific membrane antigen (PSMA)-617. [161Tb]Tb-PSMA-617 (7.4 MBq/nmol) demonstrated a radiochemical yield of 97.99 ± 2.01% and hydrophilicity. [161Tb]Tb-PSMA-617 was also shown to have good stability, with a radiochemical yield of over 95% up to 72 h. In vitro, [161Tb]Tb-PSMA-617 exhibited cytotoxicity on LNCaP cells but not on PC3 cells. In vivo, scintigraphy imaging visualized the accumulation of [161Tb]Tb-PSMA-617 in the prostate, kidneys, and bladder. The results suggest that [161Tb]Tb-PSMA-617 can be an effective radiolabeled agent for the treatment of PSMA positive foci in prostate cancer. [ABSTRACT FROM AUTHOR]

The prevalence rate of prostate cancer is very high and unfortunately causes many deaths worldwide. This study aimed to prepare [113mIn]In-PSMA as a novel agent for single photon emission computed tomography (SPECT) imaging of prostate cancer. 113mIn was eluted from an in-house made 113Sn/113mIn generator in chloride form, and its radionuclide, chemical and radiochemical purities was studied. [113mIn]In-PSMA was prepared with radiochemical purity (RCP) > 99 % under optimal labeling conditions. The biodistribution of the labeled compound was studied in normal rats, showed the major activity in the urine and kidneys as the main excretion route from the body. Considerable uptake was observed in the prostate and salivary glands as the PSMA-expressing organs. These data are in complete agreement with the other published data on PSMA-labeled compounds both in animals and humans. The results demonstrated [113mIn]In-PSMA can be considered as a good option for SPECT imaging of prostate cancer. [ABSTRACT FROM AUTHOR]

Aim: The study aims to determine the physiological and pathophysiological distribution of the radiopharmaceutical (Ga68-PSMA-617) and investigate whether there are differences in distribution according to the laboratory, histopathological and clinical findings that can affect image evaluation. Also, we aimed to determine cut-off values to distinguish physiological and pathological uptake in prostate, bone, and lymph nodes. Materials and Methods: 229 prostate cancer patients who underwent Ga68-PSMA PET/CT at our department were retrospectively analyzed. The patients were grouped according to PET/CT results, Gleason scores, PSA values, received treatments, metastatic status and other laboratory values. The SUV values of the organs, tissues, and pathological lesions of the patients in these subgroups were compared among themselves. Results: No significant difference was detected in the physiological uptake of lymph nodes and bone between the groups. In the group with patients that received androgen deprivation therapy (ADT), the bone metastasis SUV values were found to be higher and the SUV values of the submandibular gland and renal cortex were found to be lower (Mann–Whitney U, p = 0.043; 0.004; 0.01, respectively). In the group with patients who received radiotherapy, the normal prostate tissue SUV values were determined to be higher (Mann–Whitney U, p = 0.009). The SUV values of the submandibular gland, muscle, liver, and blood pool were found to be lower in the group of patients with high serum LDH values. The cut-off SUVmax value was determined to be 6.945 (sensitivity 89.6%, specificity 98.1%) for primary prostate lesion; 4.72 for lymph node metastasis; 4.25 for bone metastasis. The serum PSA cut-off value to distinguish the negative/positive groups was found to be 1,505 (sensitivity 79.7%, specificity 77.3%). Conclusion: In conclusion, PSMA-617 demonstrates a similar biodistribution with other PSMA ligands. The physiological uptake of lymph nodes and bone which are mostly metastasized in prostate cancer, are not affected by the factors we examined. It should be kept in mind that the normal prostate tissue uptake may increase in patients receiving radiotherapy, and the physiological/pathological uptake of the organs may differ due to the changes in PSMA expression in patients receiving ADT, tumor burden, and kidney function may affect the biodistribution. [ABSTRACT FROM AUTHOR]

Radionuclide therapy targeting prostate-specific membrane antigen (PSMA) is a promising option for metastatic castration-resistant prostate cancer. Clinical experience using 177Lu or 225Ac has demonstrated encouraging treatment responses; however, responses are not durable. Dual-isotope combinations, or tandem approaches, may improve tolerability while retaining a high tumor dose. In this study, we directly compared α- versus β-particle treatment, as well as a combination thereof, at different stages of disease in a murine model of disseminated prostate cancer. Methods: First, to determine comparable injected activities from 177Lu- and 225Ac-PSMA-617, ex vivo biodistribution studies were performed at 5 time points after treatment of C4-2 subcutaneous tumor-bearing NSG mice. To establish a more representative model of metastatic prostate cancer, NSG mice were inoculated with luciferase-expressing C4-2 cells in the left ventricle, leading to disseminated visceral and bone lesions. At either 3 or 5 wk after inoculation, the mice were treated with equivalent tumor dose-depositing activities of 177Lu- or 225Ac-PSMA-617 alone or in combination (35 MBq of 177Lu, 40 kBq of 225Ac, or 17 MBq of 177Lu + 20 kBq 225Ac; 10/group). Disease burden was assessed by weekly bioluminescence imaging. Treatment efficacy was evaluated using whole-body tumor burden and overall survival. Results: The ex vivo biodistribution studies revealed that 35 MBq of 177Lu and 40 kBq of 225Ac yield equivalent absorbed tumor doses in a subcutaneous C4-2 model. The disease burden of mice treated at 3 wk after inoculation (microscopic disease) with 177Lu was not significantly different from that of untreated mice. However, 225Ac-PSMA-617 both as a single agent and in combination with 177Lu (17 MBq of 177Lu + 20 kBq of 225Ac) were associated with significant whole-body tumor growth retardation and survival benefit (overall survival, 8.3 wk for nontreatment, 9.4 wk for 177Lu, 15.3 wk for 225Ac alone, and 14.1 wk for tandem therapy). When treated at 5 wk after inoculation (macroscopic disease), all treatment groups showed retarded tumor growth and improved survival, with no significant differences between 225Ac alone and administration of half the 225Ac activity in tandem with 177Lu (overall survival, 7.9 wk for nontreatment, 10.3 wk for 177Lu, 14.6 wk for 225Ac alone, and 13.2 wk for tandem therapy). Conclusion: Treatment of a disseminated model of prostate cancer with simultaneous 225Ac- and 177Lu-PSMA-617 results in significantly decreased tumor growth compared with 177Lu, which was ineffective as a single agent against microscopic lesions. Mice treated later in the disease progression and bearing macroscopic, millimeter-sized lesions experienced significant tumor growth retardation and survival benefit in both monoisotopic and tandem regimens of 177Lu and 225Ac. Although the greatest benefits were observed with the single agent 225Ac, the tandem arm experienced no significant difference in disease burden or survival benefit, suggesting that the reduced activity of 225Ac was adequately compensated in the tandem arm. The superior therapeutic efficacy of 225Ac in this model suggests a preference for α-emitters alone, or possibly in combination, in the microscopic disease setting.

225Ac-targeted α-radiotherapy is a promising approach to treating malignancies, including prostate cancer. However, α-emitting isotopes are difficult to image because of low administered activities and a low fraction of suitable γ-emissions. The in vivo generator 134Ce/134La has been proposed as a potential PET imaging surrogate for the therapeutic nuclides 225Ac and 227Th. In this report, we detail efficient radiolabeling methods using the 225Ac-chelators DOTA and MACROPA. These methods were applied to radiolabeling of prostate cancer imaging agents, including PSMA-617 and MACROPA-PEG4-YS5, for evaluation of their in vivo pharmacokinetic characteristics and comparison to the corresponding 225Ac analogs. Methods: Radiolabeling was performed by mixing DOTA/MACROPA chelates with 134Ce/134La in NH4OAc, pH 8.0, at room temperature, and radiochemical yields were monitored by radio-thin-layer chromatography. In vivo biodistributions of 134Ce-DOTA/MACROPA.NH2 complexes were assayed through dynamic small-animal PET/CT imaging and ex vivo biodistribution studies over 1 h in healthy C57BL/6 mice, compared with free 134CeCl3 In vivo, preclinical imaging of 134Ce-PSMA-617 and 134Ce-MACROPA-PEG4-YS5 was performed on 22Rv1 tumor-bearing male nu/nu-mice. Ex vivo biodistribution was performed for 134Ce/225Ac-MACROPA-PEG4-YS5 conjugates. Results: 134Ce-MACROPA.NH2 demonstrated near-quantitative labeling with 1:1 ligand-to-metal ratios at room temperature, whereas a 10:1 ligand-to-metal ratio and elevated temperatures were required for DOTA. Rapid urinary excretion and low liver and bone uptake were seen for 134Ce/225Ac-DOTA/MACROPA. NH2 conjugates in comparison to free 134CeCl3 confirmed high in vivo stability. An interesting observation during the radiolabeling of tumor-targeting vectors PSMA-617 and MACROPA-PEG4-YS5-that the daughter 134La was expelled from the chelate after the decay of parent 134Ce-was confirmed through radio-thin-layer chromatography and reverse-phase high-performance liquid chromatography. Both conjugates, 134Ce-PSMA-617 and 134Ce-MACROPA-PEG4-YS5, displayed tumor uptake in 22Rv1 tumor-bearing mice. The ex vivo biodistribution of 134Ce-MACROPA.NH2, 134Ce-DOTA and 134Ce-MACROPA-PEG4-YS5 corroborated well with the respective 225Ac-conjugates. Conclusion: These results demonstrate the PET imaging potential for 134Ce/134La-labeled small-molecule and antibody agents. The similar 225Ac and 134Ce/134La-chemical and pharmacokinetic characteristics suggest that the 134Ce/134La pair may act as a PET imaging surrogate for 225Ac-based radioligand therapies.

Abstract Background In the last decade the development of new PSMA-ligand based radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research. The most promising derivative in terms of interaction with the antigen and clinical properties has been found to be “PSMA-617”, and its lutetium-177 radiolabelled version has recently been approved by EU and USA regulatory agencies for therapeutic purposes. For the above reasons, the development of new derivatives of PSMA-617 radiolabelled with fluorine-18 may still be of great interest. This paper proposes the comparison of two different PSMA-617 derivatives functionalized with NODA and RESCA chelators, respectively, radiolabelled via [18F]AlF2+ complexation. Results The organic synthesis of two PSMA-617 derivatives and their radiolabelling via [18F]AlF2+ complexation resulted to proceed efficiently and successfully. Moreover, stability in solution and in plasma has been evaluated. The whole radiosynthesis procedure has been fully automated, and the final products have been obtained with radiochemical yield and purity potentially suitable for clinical studies. The biodistribution of the two derivatives was performed both in prostate cancer and glioma tumour models. Compared with the reference [18F]F-PSMA-1007 and [18F]F-PSMA-617-RESCA, [18F]F-PSMA-617-NODA derivative showed a higher uptake in both tumors, faster clearance in non-target organs, and lower uptake in salivary glands. Conclusion PSMA-617 NODA and RESCA derivatives were radiolabelled successfully via [18F]AlF2+ chelation, the former being more stable in solution and human plasma. Moreover, preclinical biodistribution studies showed that [18F]F-PSMA-617-NODA might be of potential interest for clinical applications.

Background: In the last decade the development of new PSMA-ligand based radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research. The most promising derivative in terms of interaction with the antigen and clinical properties has been found to be "PSMA-617", and its lutetium-177 radiolabelled version has recently been approved by EU and USA regulatory agencies for therapeutic purposes. For the above reasons, the development of new derivatives of PSMA-617 radiolabelled with fluorine-18 may still be of great interest. This paper proposes the comparison of two different PSMA-617 derivatives functionalized with NODA and RESCA chelators, respectively, radiolabelled via [18F]AlF2+ complexation. Results: The organic synthesis of two PSMA-617 derivatives and their radiolabelling via [18F]AlF2+ complexation resulted to proceed efficiently and successfully. Moreover, stability in solution and in plasma has been evaluated. The whole radiosynthesis procedure has been fully automated, and the final products have been obtained with radiochemical yield and purity potentially suitable for clinical studies. The biodistribution of the two derivatives was performed both in prostate cancer and glioma tumour models. Compared with the reference [18F]F-PSMA-1007 and [18F]F-PSMA-617-RESCA, [18F]F-PSMA-617-NODA derivative showed a higher uptake in both tumors, faster clearance in non-target organs, and lower uptake in salivary glands. Conclusion: PSMA-617 NODA and RESCA derivatives were radiolabelled successfully via [18F]AlF2+ chelation, the former being more stable in solution and human plasma. Moreover, preclinical biodistribution studies showed that [18F]F-PSMA-617-NODA might be of potential interest for clinical applications. [ABSTRACT FROM AUTHOR]

[177Lu]Lu-PSMA-617 has recently been successfully approved by the FDA, the MHRA, Health Canada and the EMA as Pluvicto®. However, salivary gland (SG) and kidney toxicities account for its main dose-limiting side-effects, while its corresponding uptake and retention mechanisms still remain elusive. Recently, the presence of different ATP-binding cassette (ABC) transporters, such as human breast cancer resistance proteins (BCRP), multidrug resistance proteins (MDR1), multidrug-resistance-related proteins (MRP1, MRP4) and solute cassette (SLC) transporters, such as multidrug and toxin extrusion proteins (MATE1, MATE2-K), organic anion transporters (OAT1, OAT2v1, OAT3, OAT4) and peptide transporters (PEPT2), has been verified at different abundances in human SGs and kidneys. Therefore, our aim was to assess whether [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 are substrates of these ABC and SLC transporters. For in vitro studies, the novel isotopologue ([α,β-3H]Nal)Lu-PSMA-617 was used in cell lines or vesicles expressing the aforementioned human ABC and SLC transporters for inhibition and uptake studies, respectively. The corresponding probe substrates and reference inhibitors were used as controls. Our results indicate that [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 are neither inhibitors nor substrates of the examined transporters. Therefore, our results show that human ABC and SLC transporters play no central role in the uptake and retention of [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 in the SGs and kidneys nor in the observed toxicities. [ABSTRACT FROM AUTHOR]

Introduction. The use of radiopharmaceuticals for targeted radionuclide therapy (TRT), the efficacy of which was established during clinical trials, is safe and effective for various pathological conditions, including cancer. The main feature of therapeutic radiopharmaceuticals (RPs) is the use of β–- and α-emitting radionuclides (RNs) in the finished dosage form (FD). Among the radionuclides used for radionuclide therapy, lutetium-177 is currently one of the most popular in clinical practice because of its chemical and nuclear characteristics. The list of RPs based on lutetium-177 is constantly expanding, and Lutathera® ([177Lu]Lu-DOTA-TATE) and Pluvicto™ ([177Lu]Lu-PSMA-617) have been approved for clinical use in several countries.Text. Because of the high activity of RNs in a single dose of therapeutic RPs (up to 8 GBq in a monodose for 177Lu), ionizing radiation of the used RNs leads to a decrease in RPs quality owing to radiolytic degradation of the vector molecule. This leads to a decreased specific accumulation of radioactivity in the foci of pathology, reduced therapeutic effect, and potentially increases the risk of radiotoxicity to non-target organs and tissues. The degree and intensity of radiolytic degradation of the vector molecule and, consequently, the shelf life of RPs depend on many factors, among which the activity concentration of the radionuclide in the preparation, its half-life, and the energy of the emitted particles are the most important. To suppress the effects of radiolysis, various excipients with antioxidant (radioprotective) properties were introduced into the compositions of the finished dosage forms. Among the substances studied, the most popular were gentisic acid, ascorbic acid, and ethanol. In this work, the advantages and disadvantages of various antioxidants and their combinations used in therapeutic RPs were considered in lutetium-177 preparations.Conclusion. Selection of the optimal composition of the dosage form is an urgent task, as it will ensure high-quality RPs both at the time of preparation and during the shelf life and delivery to the end user, which will greatly facilitate the use and centralized supply of therapeutic RPs. The necessity of creating a unified approach for the selection of antioxidants at the pharmaceutical development stage of radiopharmaceuticals is shown. For this purpose, an approach combining studies of radical reaction kinetics with studies of radiation-chemical yields of radiolysis products under identical or maximally similar conditions with subsequent verification of the stability of RPs dosage form seems to be very promising and has proven to be effective. In contrast, the empirical approach, which implies the selection of radioprotectors based on a direct study of their influence on the preservation of the level of radiochemical purity, is suboptimal because of the high market value of both radionuclides and non-radioactive precursors.

BackgroundPSMA-TO-1 ("Tumor-Optimized-1") is a novel PSMA ligand with longer circulation time than PSMA-617. We compared the biodistribution in subcutaneous tumor-bearing mice of PSMA-TO-1, PSMA-617 and PSMA-11 when labeled with 68Ga and 177Lu, and the survival after treatment with 225Ac-PSMA-TO-1/-617 in a murine model of disseminated prostate cancer. We also report dosimetry data of 177Lu-PSMA-TO1/-617 in prostate cancer patients.MethodsFirst, PET images of 68Ga-PSMA-TO-1/-617/-11 were acquired on consecutive days in three mice bearing subcutaneous C4-2 xenografts. Second, 50 subcutaneous tumor-bearing mice received either 30 MBq of 177Lu-PSMA-617 or 177Lu-PSMA-TO-1 and were sacrificed at 1, 4, 24, 48 and 168 h for ex vivo gamma counting and biodistribution. Third, mice bearing disseminated lesions via intracardiac inoculation were treated with either 40 kBq of 225Ac-PSMA-617, 225Ac-PSMA-TO-1, or remained untreated and followed for survival. Additionally, 3 metastatic castration-resistant prostate cancer patients received 500 MBq of 177Lu-PSMA-TO-1 under compassionate use for dosimetry purposes. Planar images with an additional SPECT/CT acquisition were acquired for dosimetry calculations.ResultsTumor uptake measured by PET imaging of 68Ga-labeled agents in mice was highest using PSMA-617, followed by PSMA-TO-1 and PSMA-11. 177Lu-PSMA tumor uptake measured by ex vivo gamma counting at subsequent time points tended to be greater for PSMA-TO-1 up to 1 week following treatment (p > 0.13 at all time points). This was, however, accompanied by increased kidney uptake and a 26-fold higher kidney dose of PSMA-TO-1 compared with PSMA-617 in mice. Mice treated with a single-cycle 225Ac-PSMA-TO-1 survived longer than those treated with 225Ac-PSMA-617 and untreated mice, respectively (17.8, 14.5 and 7.7 weeks, respectively; p

Prostate-specific membrane antigen (PSMA) represents a promising target for PSMA-overexpressing diseases, especially prostate cancer-a common type of cancer among men worldwide. In response to the challenges in tackling prostate cancers, several promising PSMA inhibitors from a variety of molecular scaffolds (e.g., phosphorous-, thiol-, and urea-based molecules) have been developed. In addition, PSMA inhibitors bearing macrocyclic chelators have attracted interest due to their favorable pharmacokinetic properties. Recently, conjugating a small PSMA molecule inhibitor-bearing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator, as exemplified by [177Lu]Lu-PSMA-617 could serve as a molecular imaging probe and targeted radioligand therapy (TRT) of metastatic castration resistant prostate cancer (mCRPC). Hence, studies related to mCRPC have drawn global attention. In this review, the recent development of PSMA ligand-617-labeled with 177Lu for the management of mCRPC is presented. Its molecular mechanism of action, safety, efficacy, and future direction are also described.

Metastatic castration‐resistant prostate cancer (mCRPC) remains a challenging condition to treat despite recent advancements. This retrospective study aimed to assess the activity and tolerability of Lutetium‐177 (Lu‐177) PSMA‐617 radioligand therapy (RLT) in mCRPC patients across multiple cancer centers in Turkey. The study included 165 patients who received at least one cycle of Lu‐177 PSMA‐617 RLT, with the majority having bone metastases and undergone prior treatments. Prostate‐specific antigen (PSA) levels were assessed before each treatment cycle, and the biochemical response was evaluated in accordance with the Prostate Cancer Work Group 3 Criteria. The PSA decline of ≥50% was classified as a response, while an increase of ≥25% in PSA levels was indicative of progressive disease. Neither response nor progression was considered as stable disease. The Lu‐177 PSMA‐617 RLT led to a significant PSA response, with 50.6% of patients achieving a >50% decrease in PSA levels. Median overall survival (OS) and progression‐free survival were 13.5 and 8.2 months, respectively. Patients receiving Lu‐177 PSMA‐617 RLT in combination with androgen receptor pathway inhibitors (ARPIs) had a higher OS compared to those receiving Lu‐177 PSMA‐617 RLT alone (18.2 vs 12.3 months, P =.265). The treatment was generally well‐tolerated, with manageable side effects such as anemia and thrombocytopenia. This study provides real‐world evidence supporting the effectiveness and safety of Lu‐177 PSMA‐617 RLT in mCRPC patients, particularly when used in combination with ARPIs. These findings contribute to the growing body of evidence on the potential benefits of PSMA‐targeted therapies in advanced prostate cancer. [ABSTRACT FROM AUTHOR]

The human prostate–specific membrane antigen (PSMA) is substantially up-regulated in metastatic prostate cancer (PCa) cells. PSMA can be targeted by 177Lu conjugated to PSMA-617, a high-affinity ligand for the PSMA. The binding of the radioligand, 177Lu-PSMA-617, results in its internalisation and delivery of β-radiation into the cancer cells. However, PSMA-617, a component of the final product in the synthesis of the radioligand, may also play a role in the pathophysiology of PCa cells. The present study aimed to clarify the effects of PSMA-617 (10, 50 and 100 nM) on the expression of PSMA in PSMA-positive LNCaP cells, their proliferation, 177Lu-PSMA-617-induced cell death by WST-1 and lactate dehydrogenase assays, immunohistochemistry, western blotting, immunofluorescence staining and uptake of 177Lu-PSMA-617. PSMA-617 at 100 nM concentration induced cell-growth arrest, down-regulated cyclin D1 and cyclin E1 (by 43 and 36%, respectively) and up-regulated the cyclin-dependent kinase inhibitor p21Waf1/Cip1 (by 48%). Immunofluorescence staining demonstrated reduced content of DNA, pointing to a lower rate of cell division. PSMA-617 (up to 100 nM) did not alter the uptake of 177Lu-PSMA-617 into the LNCaP cells. Interestingly, simultaneous treatment with 177Lu-PSMA-617 and PSMA-617 for 24 and 48 h substantially potentiated the cell-death promoting effects of the radioligand. In conclusion, the combination of impeding tumour cell proliferation by PSMA-617 and its potentiation of the radiation-induced cell death brought about by 177Lu-PSMA-617 in PCa cells may considerably improve the outcome of the radiation therapy with 177Lu-PSMA-617, especially in patients with decreased radiosensitivity of PCa cells to the radioligand. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA) represents a promising target for PSMAoverexpressing diseases, especially prostate cancer-a common type of cancer among men worldwide. In response to the challenges in tackling prostate cancers, several promising PSMA inhibitors from a variety of molecular scaffolds (e.g., phosphorous-, thiol-, and urea-based molecules) have been developed. In addition, PSMA inhibitors bearing macrocyclic chelators have attracted interest due to their favorable pharmacokinetic properties. Recently, conjugating a small PSMA molecule inhibitor-bearing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator, as exemplified by [177Lu]Lu-PSMA-617 could serve as a molecular imaging probe and targeted radioligand therapy (TRT) of metastatic castration resistant prostate cancer (mCRPC). Hence, studies related to mCRPC have drawn global attention. In this review, the recent development of PSMA ligand-617-labeled with 177Lu for the management of mCRPC is presented. Its molecular mechanism of action, safety, efficacy, and future direction are also described. [ABSTRACT FROM AUTHOR]

Introduction: Central to targeted radionuclide imaging and therapy of prostate cancer (PCa) are prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals. Gastrin-releasing peptide receptor (GRPR) targeting has been proposed as a potential additional approach for PCa theranostics. The aim of this study was to investigate to what extent and at what stage of the disease GRPR-targeting applications can complement PSMA-targeting theranostics in the management of PCa. Methods: Binding of the GRPR- and PSMA-targeting radiopharmaceuticals [177Lu]Lu-NeoB and [177Lu]Lu-PSMA-617, respectively, was evaluated and compared on tissue sections of 20 benign prostatic hyperplasia (BPH), 16 primary PCa and 17 progressive castration-resistant PCa (CRPC) fresh frozen tissue specimens. Hematoxylin-eosin and alpha-methylacyl-CoA racemase stains were performed to identify regions of prostatic adenocarcinoma and potentially high-grade prostatic intraepithelial neoplasia. For a subset of primary PCa samples, RNA in situ hybridization (ISH) was used to identify target mRNA expression in defined tumor regions. Results: The highest median [177Lu]Lu-NeoB binding was observed in primary PCa samples, while median and overall [177Lu]Lu-PSMA-617 binding was highest in CRPC samples. The highest [177Lu]Lu-NeoB binding was observed in 3/17 CRPC samples of which one sample showed no [177Lu]Lu-PSMA-617 binding. RNA ISH analyses showed a trend between mRNA expression and radiopharmaceutical binding, and confirmed the distinct GRPR and PSMA expression patterns in primary PCa observed with radiopharmaceutical binding Conclusion: Our study emphasizes that GRPR-targeting approaches can contribute to improved PCa management and complement currently applied PSMA-targeting strategies in both early and late stage PCa. [ABSTRACT FROM AUTHOR]

Radiochemical purity (RCP) is one of the key quality criteria for radiopharmaceuticals (RPs) used in clinical practice. The results of RCP measurements depend on the analytical technique, as well as detection parameters, which are specific to a particular analytical system. When reviewing literature data on the synthesis, pharmaceutical development, preclinical and clinical trials of the same radiopharmaceutical by different authors, one may note significant variability in the RCP values obtained. Hence, it is important to carefully select analysis parameters and study their influence on the results. The aim of the study was to compare previously published and self-developed procedures for RCP analysis of 177Lu-RPs in terms of their efficiency in the detection and quantification of possible radiochemical impurities, as well as to determine the analytical system parameters that have a significant impact on the interpretation of the analysis results, using [177Lu]Lu–PSMA-617 as a case study. Materials and methods: the study used samples of [177Lu]Lu–PSMA-617 with a volume activity of lutetium-177 of 150–4800 MBq/mL, containing 10–100 µmol/L of the PSMA-617 precursor and 30 mmol/L of sodium acetate as a buffering solution (pH 4.5). The samples were tested by high-performance liquid chromatography (HPLC) and thin-layer chromatography in the conditions described in the literature and developed in the course of the work. Results: the study showed a significant influence of the chosen analytical procedure on the results of [177Lu]Lu–PSMA-617 RCP assessment. The profile of possible radiochemical impurities requires the use of high-resolution HPLC techniques. Conclusions: the analytical procedure developed and applied by the authors is quite effective. The results of RCP assessment are influenced by the detection system parameters, such as the length and inner diameter of the flow cell and the means of analytical signal processing (peak extraction parameters, smoothing parameters, and noise subtraction/suppression). This fact necessitates validation considering the characteristics of a particular analytical system and demonstrates the need to assess interlaboratory precision in the framework of the implementation and verification of analytical procedures.

In the field of nuclear medicine, the β+ -emitting 43Sc and β− -emitting 47Sc are promising candidates in cancer diagnosis and targeted radionuclide therapy (TRT) due to their favorable decay schema and shared pharmacokinetics as a true theranostic pair. Additionally, scandium is a group-3 transition metal (like 177Lu) and exhibits affinity for DOTA-based chelators, which have been studied in depth, making the barrier to implementation lower for 43/47Sc than for other proposed true theranostics. Before 43/47Sc can see widespread pre-clinical evaluation, however, an accessible production methodology must be established and each isotope's radiolabeling and animal imaging capabilities studied with a widely utilized tracer. As such, a simple means of converting an 18 MeV biomedical cyclotron to support solid targets and produce 43Sc via the 42Ca(d,n)43Sc reaction has been devised, exhibiting reasonable yields. The NatTi(γ,p)47Sc reaction is also investigated along with the successful implementation of chemical separation and purification methods for 43/47Sc. The conjugation of 43/47Sc with PSMA-617 at specific activities of up to 8.94 MBq/nmol and the subsequent imaging of LNCaP-ENZaR tumor xenografts in mouse models with both 43/47Sc-PSMA-617 are also presented. [ABSTRACT FROM AUTHOR]

Abstract Background PSMA-TO-1 (“Tumor-Optimized-1”) is a novel PSMA ligand with longer circulation time than PSMA-617. We compared the biodistribution in subcutaneous tumor-bearing mice of PSMA-TO-1, PSMA-617 and PSMA-11 when labeled with 68Ga and 177Lu, and the survival after treatment with 225Ac-PSMA-TO-1/-617 in a murine model of disseminated prostate cancer. We also report dosimetry data of 177Lu-PSMA-TO1/-617 in prostate cancer patients. Methods First, PET images of 68Ga-PSMA-TO-1/-617/-11 were acquired on consecutive days in three mice bearing subcutaneous C4-2 xenografts. Second, 50 subcutaneous tumor-bearing mice received either 30 MBq of 177Lu-PSMA-617 or 177Lu-PSMA-TO-1 and were sacrificed at 1, 4, 24, 48 and 168 h for ex vivo gamma counting and biodistribution. Third, mice bearing disseminated lesions via intracardiac inoculation were treated with either 40 kBq of 225Ac-PSMA-617, 225Ac-PSMA-TO-1, or remained untreated and followed for survival. Additionally, 3 metastatic castration-resistant prostate cancer patients received 500 MBq of 177Lu-PSMA-TO-1 under compassionate use for dosimetry purposes. Planar images with an additional SPECT/CT acquisition were acquired for dosimetry calculations. Results Tumor uptake measured by PET imaging of 68Ga-labeled agents in mice was highest using PSMA-617, followed by PSMA-TO-1 and PSMA-11. 177Lu-PSMA tumor uptake measured by ex vivo gamma counting at subsequent time points tended to be greater for PSMA-TO-1 up to 1 week following treatment (p > 0.13 at all time points). This was, however, accompanied by increased kidney uptake and a 26-fold higher kidney dose of PSMA-TO-1 compared with PSMA-617 in mice. Mice treated with a single-cycle 225Ac-PSMA-TO-1 survived longer than those treated with 225Ac-PSMA-617 and untreated mice, respectively (17.8, 14.5 and 7.7 weeks, respectively; p

IntroductionCentral to targeted radionuclide imaging and therapy of prostate cancer (PCa) are prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals. Gastrin-releasing peptide receptor (GRPR) targeting has been proposed as a potential additional approach for PCa theranostics. The aim of this study was to investigate to what extent and at what stage of the disease GRPR-targeting applications can complement PSMA-targeting theranostics in the management of PCa.MethodsBinding of the GRPR- and PSMA-targeting radiopharmaceuticals [177Lu]Lu-NeoB and [177Lu]Lu-PSMA-617, respectively, was evaluated and compared on tissue sections of 20 benign prostatic hyperplasia (BPH), 16 primary PCa and 17 progressive castration-resistant PCa (CRPC) fresh frozen tissue specimens. Hematoxylin-eosin and alpha-methylacyl-CoA racemase stains were performed to identify regions of prostatic adenocarcinoma and potentially high-grade prostatic intraepithelial neoplasia. For a subset of primary PCa samples, RNA in situ hybridization (ISH) was used to identify target mRNA expression in defined tumor regions.ResultsThe highest median [177Lu]Lu-NeoB binding was observed in primary PCa samples, while median and overall [177Lu]Lu-PSMA-617 binding was highest in CRPC samples. The highest [177Lu]Lu-NeoB binding was observed in 3/17 CRPC samples of which one sample showed no [177Lu]Lu-PSMA-617 binding. RNA ISH analyses showed a trend between mRNA expression and radiopharmaceutical binding, and confirmed the distinct GRPR and PSMA expression patterns in primary PCa observed with radiopharmaceutical binding.ConclusionOur study emphasizes that GRPR-targeting approaches can contribute to improved PCa management and complement currently applied PSMA-targeting strategies in both early and late stage PCa.

This study was performed to synthesize multimodal radiopharmaceutical designed for the diagnosis and treatment of prostate cancer. To achieve this goal, superparamagnetic iron oxide (SPIO) nanoparticles were used as a platform for targeting molecule (PSMA-617) and for complexation of two scandium radionuclides, 44Sc for PET imaging and 47Sc for radionuclide therapy. TEM and XPS images showed that the Fe3O4 NPs have a uniform cubic shape and a size from 38 to 50 nm. The Fe3O4 core are surrounded by SiO2 and an organic layer. The saturation magnetization of the SPION core was 60 emu/g. However, coating the SPIONs with silica and polyglycerol reduces the magnetization significantly. The obtained bioconjugates were labeled with 44Sc and 47Sc, with a yield higher than 97%. The radiobioconjugate exhibited high affinity and cytotoxicity toward the human prostate cancer LNCaP (PSMA+) cell line, much higher than for PC-3 (PSMA-) cells. High cytotoxicity of the radiobioconjugate was confirmed by radiotoxicity studies on LNCaP 3D spheroids. In addition, the magnetic properties of the radiobioconjugate should allow for its use in guide drug delivery driven by magnetic field gradient. [ABSTRACT FROM AUTHOR]

The radiolytic degradation of vector molecules is a major factor affecting the shelf life of therapeutic radiopharmaceuticals. The development of time-stable dosage forms of radiopharmaceuticals is the key to their successful implementation in clinical practice. Using [177Lu]Lu-PSMA-617 molecule as an example, the time dependence of the change in radiochemical purity (RCP, %) under radiolysis conditions was studied. The dependence of [177Lu]Lu-PSMA-617 radiolysis on parameters such as time, radionuclide activity, buffer agent concentration, precursor amount, and preparation volume was evaluated. It was shown that the absorbed dose was the dominant factor influencing the RCP. The RCP value is inversely proportional to the absorbed dose in the [177Lu]Lu-PSMA-617 preparation and has an exponential dependence. The lutetium-177 dose factor ψ (Gy·mL·MBq−1) and PSMA-617 concentration-dependent dose constant κ (Gy−1) were evaluated for absorbed dose estimation via computer modeling, chemical dosimetry, and radiochemical purity monitoring under various conditions. The further refinement and application of the dependencies found can be useful for predicting the RCP value at the stage of optimizing the composition of the finished dosage form of therapeutic radiopharmaceuticals. The influence of the buffer agent (sodium acetate) concentration on [177Lu]Lu-PSMA-617 radiolytic degradation was shown and should be considered both when developing a dosage form, and when comparing the results of independent studies. The effectiveness of the addition of various stabilizing agents, such as DMSA, cysteine, gentisic acid, vanillin, methionine, adenine, dobesilic acid, thymine, uracil, nicotinamide, meglumine, and mannitol, in suppressing the effects of radiolysis was evaluated. [ABSTRACT FROM AUTHOR]

Purpose: Recently, Pluvicto™ ([177Lu]Lu-PSMA-617), a small-molecule prostate-specific membrane antigen (PSMA) radioligand therapeutic, has been approved by the FDA in metastatic castration-resistant prostate cancer. Pluvicto™ and other PSMA-targeting radioligand therapeutics (RLTs) have shown side effects due to accumulation in certain healthy tissues, such as salivary glands and kidney. Until now, the molecular mechanism underlying the undesired accumulation of PSMA-targeting RLTs had not been elucidated. Methods: We compared the sequence of PSMA with the entire human proteome to identify proteins closely related to the target. We have identified glutamate carboxypeptidase III (GCPIII), N-acetylated alpha-linked acidic dipeptidase like 1 (NAALADL-1), and transferrin receptor 1 (TfR1) as extracellular targets with the highest similarity to PSMA. The affinity of compound 1 for PSMA, GCPIII, NAALADL-1, and TfR1 was measured by fluorescence polarization. The expression of the putative anti-target GCPIII was assessed by immunofluorescence on human salivary glands and kidney, using commercially available antibodies. Results: A fluorescent derivative of Pluvicto™ (compound 1) bound tightly to PSMA and to GCPIII in fluorescence polarization experiments, while no interaction was observed with NAALADL-1 and TfR1. Immunofluorescence analysis revealed abundant expression of GCPIII both in healthy human kidney and salivary glands. Conclusion: We conclude that the membranous expression of GCPIII in kidney and salivary gland may be the underlying cause for unwanted accumulation of Pluvicto™ and other Glu-ureido PSMA radio pharmaceuticals in patients. [ABSTRACT FROM AUTHOR]

The paper presents the results of a study on the radiolytic degradation of vector molecules in radiopharmaceuticals, caused by ionizing radiation from the radionuclide used in the preparations, in comparison with the equal dose of external X-ray irradiation. The dose factors for therapeutic radionuclides samarium-153 and lutetium-177 in aqueous solutions were estimated in geometry simulating the finished dosage form of radiopharmaceuticals (standard injection vial) both by computational methods (in silico) and applying chemical dosimetry. Irradiation with external X-ray source to doses formed in volume of therapeutic radiopharmaceuticals with given radioactivity concentration was performed on an LNK-268 X-ray unit. Using the [153Sm]Sm-PSMA-617 and [177Lu]Lu-PSMA-617 radiopharmaceuticals as an instance, we compared the degree of radiolytic degradation and the profiles of radiolytic impurities formed as a result of both external X-ray irradiation and autoradiolysis. Qualitative coincidence of the impurity profiles formed in both cases was noted. It has been shown that external X-ray radiation can be used to simulate the autoradiolysis processes of radiopharmaceuticals if additional corrections are made for the type of radiation and dose rate. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate-specific membrane antigen (PSMA) radioligands have proven effective to treat patients with metastatic castration-resistant prostate cancer. Targeted α-therapy using actinium-225 has been used for patients with end-stage disease who no longer responded to βࢤ-therapy through the use of 177Lu-based radioligand therapy (RLT). In this study, we investigated and compared the therapeutic efficacy of [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617 and assessed potential undesired side effects in the preclinical setting. Due to a dedicated albumin-binding entity integrated into [225Ac]Ac-SibuDAB, this radioligand showed an enhanced blood circulation time and, hence, increased tumor uptake but also higher retention in normal tissues. The therapeutic efficacy of [225Ac]Ac-SibuDAB was enhanced as compared to that of [225Ac]Ac-PSMA-617, yet, undesired side effects were in the same range for both radioligands. Our data suggest that [225Ac]Ac-SibuDAB could be a powerful alternative to [225Ac]Ac-PSMA-617, however, the safe therapeutic window should be carefully defined in clinical dose escalation studies. In the present study, SibuDAB, an albumin-binding PSMA ligand, was investigated in combination with actinium-225 and the data were compared with those of [225Ac]Ac-PSMA-617. In vitro, [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617 showed similar tumor cell uptake and PSMA-binding affinities as their 177Lu-labeled counterparts. The in vitro binding to serum albumin in mouse and human blood plasma, respectively, was 2.8-fold and 1.4-fold increased for [225Ac]Ac-SibuDAB as compared to [177Lu]Lu-SibuDAB. In vivo, this characteristic was reflected by the longer retention of [225Ac]Ac-SibuDAB in the blood than previously seen for [177Lu]Lu-SibuDAB. Similar to [225Ac]Ac-PSMA-617, [225Ac]Ac-SibuDAB was well tolerated at 30 kBq per mouse. Differences in blood cell counts were observed between treated mice and untreated controls, but no major variations were observed between values obtained for [225Ac]Ac-SibuDAB and [225Ac]Ac-PSMA-617. [225Ac]Ac-SibuDAB was considerably more effective to treat PSMA-positive tumor xenografts than [225Ac]Ac-PSMA-617. Only 5 kBq per mouse were sufficient to eradicate the tumors, whereas tumor regrowth was observed for mice treated with 5 kBq [225Ac]Ac-PSMA-617 and only one out of six mice survived until the end of the study. The enhanced therapeutic efficacy of [225Ac]Ac-SibuDAB as compared to that of [225Ac]Ac-PSMA-617 and reasonable safety data qualify this novel radioligand as a candidate for targeted α-therapy of prostate cancer. [ABSTRACT FROM AUTHOR]

177Lu-vipivotide tetraxetan is a radiopharmaceutical that selectively targets prostate-specific membrane antigen (PSMA) and delivers beta-radiations to kill prostate cancer cells. Extensive experience outside the United States as well as randomized phase II and phase III data demonstrate that 177Lu-vipivotide tetraxetan is a safe, generally well tolerated, and effective therapy for men with mCRPC. 177Lu-vipivotide tetraxetan was approved by the FDA in March 2022 for the treatment of PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) after androgen receptor pathway inhibition and taxane-based chemotherapy based on the results of the VISION trial. This review discusses the development and studies leading to the approval of 177Lu-vipivotide tetraxetan. In all, 177Lu-vipivotide tetraxetan is an exciting new tool in the arsenal for men with mCRPC after novel androgen pathway inhibitors and at least one taxane chemotherapy. Optimal selection of patients, sequencing of 177Lu-vipivotide tetraxetan with the other agents available to treat mCRPC, and the use of dosimetry are current areas of interest with great potential and opportunities for further individual patient optimization using the tools of theranostics. [ABSTRACT FROM AUTHOR]

Purpose: Lutetium labelled prostate-specific membrane antigen radioligand therapy (Lu-PSMA RLT) has shown pleasing early results in management of high-volume metastatic castration resistant prostate cancer (mCRPC), but its role in the early treatment of men with only lymph node metastasis (LNM) is unknown. The aim was to assess the outcome of Lu-PSMA RLT earlier in the treatment of men with only LNM. Materials and Methods: Single institution retrospective review of men with only LNM on staging Ga-PSMA PET PSMA who proceeded with Lu-PSMA RLT. Results: There were 17 men with only LNM, including 13 with mCRPC and 3 who were both hormone and chemotherapy naïve. The median PSA was 3.7 (0.46–120 ng/mL). A PSA decline of ≥50% occurred in 10/17 (58.8%), decreasing to

Background: Labelled with lutetium-177, the urea-based small molecules PSMA I&T and PSMA-617 are the two agents most frequently used for radioligand therapy (RLT) in patients with advanced metastatic castration-resistant and prostate-specific membrane antigen (PSMA) expressing prostate cancer (mCRPC). In this matched-pair analysis, we aimed to compare the toxicity and efficacy of both agents for PSMA-directed RLT. Materials and methods: A total of 110 mCRPC patients from two centres were accrued, 55 individuals treated with [177Lu]Lu-PSMA I&T, and a matched cohort of 55 patients treated with [177Lu]Lu-PSMA-617. Matching criteria included age at the first cycle, Gleason score, prostate-specific antigen (PSA) values, and previous taxane-based chemotherapy. Using common terminology criteria for adverse events (CTCAE v. 5.0), toxicity profiles were investigated (including bone marrow and renal toxicity). Overall survival (OS) between both groups was compared. Results: Toxicity assessment revealed grade III anaemia in a single patient (1.8%) for [177Lu]Lu-PSMA I&T and five (9.1%) for [177Lu]Lu-PSMA-617. In addition, one (1.9%) grade III thrombopenia for [177Lu]Lu-PSMA-617 was recorded. Apart from that, no other grade III/IV toxicities were present. A median OS of 12 months for patients treated with [177Lu]Lu-PSMA I&T did not differ significantly when compared to patients treated with [177Lu]Lu-PSMA-617 (median OS, 13 months; P = 0.89). Conclusion: In this matched-pair analysis of patients receiving one of the two agents most frequently applied for PSMA RLT, the rate of clinically relevant toxicities was low for both compounds. In addition, no relevant differences for OS were observed. [ABSTRACT FROM AUTHOR]

Rationale: Prolonged in vivo evaluation of PSMA tracers could improve tumor imaging and patient selection for 177Lu-PSMA-617 and 177Lu-PSMA-I&T. In this study, we present the radiolabeling method of PSMA-617 and PSMA-I&T with the long-lived positron emitter 89Zr to enable PET imaging up to 7 days post-injection. We compared the biodistribution of 89Zr-PSMA-617 and 89Zr-PSMA-I&T to those of 177Lu-PSMA-617 and 177Lu-PSMA-I&T, respectively, in a PSMA+ xenograft model. Moreover, we provide the first human 89Zr-PSMA-617 images. Materials and methods: PSMA ligands were labeled with 50-55 MBq [89Zr]ZrCl4 using a two-step labeling protocol. For biodistribution, BALB/c nude mice bearing PSMA+ and PSMA− xenografts received 0.6 µg (0.6–1 MBq) of 89Zr-PSMA-617, 89Zr-PSMA-I&T, 177Lu-PSMA-617, or 177Lu-PSMA-I&T intravenously. Ex vivo biodistribution and PET/SPECT imaging were performed up to 168 h post-injection. Dosimetry was performed from the biodistribution data. The patient received 90.5 MBq 89Zr-PSMA-617 followed by PET/CT imaging. Results: 89Zr-labeled PSMA ligands showed a comparable ex vivo biodistribution to its respective 177Lu-labeled counterparts with high tumor accumulation in the PSMA+ xenografts. However, using a dose estimation model for 177Lu, absorbed radiation dose in bone and kidneys differed among the 177Lu-PSMA and 89Zr-PSMA tracers. 89Zr-PSMA-617 PET in the first human patient showed high contrast of PSMA expressing tissues up to 48 h post-injection. Conclusion: PSMA-617 and PSMA-I&T were successfully labeled with 89Zr and demonstrated high uptake in PSMA+ xenografts, which enabled PET up to 168 h post-injection. The biodistribution of 89Zr-PSMA-I&T and 89Zr-PSMA-617 resembled that of 177Lu-PSMA-I&T and 177Lu-PSMA-617, respectively. The first patient 89Zr-PSMA-617 PET images were of high quality warranting further clinical investigation. [ABSTRACT FROM AUTHOR]

In the last decade, the development of new radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research, especially focusing on the prostate‐specific membrane antigen (PSMA), an antigen which is upregulated in prostate, as well as in other tumor cells. A large variety of PSMA ligands have been radiolabeled, to date. Among the various derivatives, PSMA‐617 resulted to be one of the most interesting in terms of interaction with the antigen and clinical properties, and its lutetium‐177 labeled version has recently been approved by regulatory agencies for therapeutic purposes. For this reasons, the radiolabeling with fluorine‐18 of a PSMA‐617 derivative might be of interest. Beside other methodologies to radiolabel macromolecules with fluorine‐18, the "click‐chemistry" approach resulted to be very useful, and the copper‐catalyzed azide‐alkyne cycloaddition (CuAAC) is considered one of most efficient and reliable. This paper proposes the synthesis of a suitable precursor for the radiolabeling with fluorine‐18 of a new PSMA‐617 derivative. The whole radiosynthetic procedure has been fully automated, and the final product, which proved to be stable in plasma, has been obtained with radiochemical yield and purity suitable for subsequent preclinical studies. [ABSTRACT FROM AUTHOR]

Abstract Background The AAZTA chelator and in particular its bifunctional derivative AAZTA5 was recently investigated to demonstrate unique capabilities to complex diagnostic and therapeutic trivalent radiometals under mild conditions. This study presents a comparison of 68Ga, 44Sc and 177Lu-labeled AAZTA5-PSMA-617 with DOTA-PSMA-617 analogues. We evaluated the radiolabeling characteristics, in vitro stability of the radiolabeled compounds and evaluated their binding affinity and internalization behavior on LNCaP tumor cells in direct comparison to the radiolabeled DOTA-conjugated PSMA-617 analogs. Results AAZTA5 was synthesized in a five-step synthesis and coupled to the PSMA-617 backbone on solid phase. Radiochemical evaluation of AAZTA5-PSMA-617 with 68Ga, 44Sc and 177Lu achieved quantitative radiolabeling of > 99% after less than 5 min at room temperature. Stabilities against human serum, PBS buffer and EDTA and DTPA solutions were analyzed. While there was a small degradation of the 68Ga complex over 2 h in human serum, PBS and EDTA/DTPA, the 44Sc and 177Lu complexes were stable at 2 h and remained stable over 8 h and 1 day. For all three compounds, i.e. [natGa]Ga-AAZTA5-PSMA-617, [natSc]Sc-AAZTA5-PSMA-617 and [natLu]Lu-AAZTA5-PSMA-617, in vitro studies on PSMA-positive LNCaP cells were performed in direct comparison to radiolabeled DOTA-PSMA-617 yielding the corresponding inhibition constants (Ki). Ki values were in the range of 8–31 nM values which correspond with those of [natGa]Ga-DOTA-PSMA-617, [natSc]Sc-DOTA-PSMA-617 and [natLu]Lu-DOTA-PSMA-617, i.e. 5–7 nM, respectively. Internalization studies demonstrated cellular membrane to internalization ratios for the radiolabeled 68Ga, 44Sc and 177Lu-AAZTA5-PSMA-617 tracers (13–20%IA/106 cells) in the same range as the ones of the three radiolabeled DOTA-PSMA-617 tracers (17–20%IA/106 cells) in the same assay. Conclusions The AAZTA5-PSMA-617 structure proved fast and quantitative radiolabeling with all three radiometal complexes at room temperature, excellent stability with 44Sc, very high stability with 177Lu and medium stability with 68Ga in human serum, PBS and EDTA/DTPA solutions. All three AAZTA5-PSMA-617 tracers showed binding affinities and internalization ratios in LNCaP cells comparable with that of radiolabeled DOTA-PSMA-617 analogues. Therefore, the exchange of the chelator DOTA with AAZTA5 within the PSMA-617 binding motif has no negative influence on in vitro LNCaP cell binding characteristics. In combination with the faster and milder radiolabeling features, AAZTA5-PSMA-617 thus demonstrates promising potential for in vivo application for theranostics of prostate cancer.

Introduction: Prostate-specific membrane antigen (PSMA)-based radioligand therapy (RLT) showed in a multicentre WARMTH (World Association of Radiopharmaceutical and Molecular Therapy) study that the presence of bone metastases is a negative prognosticator for the survival. The current multicentre retrospective analysis aims to evaluate the response rate to RLT, the overall survival (OS) of patients and the safety of the treatment according to the extent of bone involvement. Methods: The study included patients with progressive metastatic castration-resistant prostate cancer (mCRPC), who underwent RLT with [177Lu]Lu-PSMA-617 and a follow-up of at least 6 months. Tumour burden in the bone was classified prior to RLT as follows: less than 6 lesions, 6–20 lesions, more than 20 lesions and diffuse involvement. The response rate was evaluated using changes of the prostate-specific antigen (PSA) after the first treatment cycle. Overall survival was calculated from the date of the first treatment. Haematological adverse events were classified according to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Results: A total of 319 males were included in the analysis. The extent of bone metastases and PSA response did not correlate significantly. Any PSA decline was observed in 73% patients; 44% showed a decline of ≥50%. The median OS of patient in the different subgroups was 18 months (less than 6 lesions), 13 months (6–20 lesions), 11 months (more than 20 lesions) and 8 months (diffuse involvement), respectively (p < 0.0001). Patients with prior Ra-223-therapy showed longer OS in all subgroups, especially in the subgroups with 6–20 lesions (OS: 16 vs. 12 months; p = 0.038) as well as diffuse involvement (OS: 11 vs. 7 months; p = 0.034). Significant negative prognosticators of OS were the existence of liver metastases in all subgroups and prior chemotherapy in patients with <6 bone lesions. Anaemia and thrombocytopenia correlated positively with the extent of bone metastases: p < 0.0001 and 0.005, respectively. No patient showed a high grade leukopenia. Conclusion: The extent of bone involvement correlated negatively with the OS after RLT; however, it showed no relevant correlation with the PSA response rate. Prior therapy with Ra-223 may have a positive impact on OS. Haematotoxicity was higher in patients with more than 20 bone lesions; nevertheless, the majority of these patients did not show a relevant haematotoxicity. [ABSTRACT FROM AUTHOR]

Purpose: Lutetium labelled prostate-specific membrane antigen radioligand therapy (Lu-PSMA RLT) has shown pleasing early results in management of high-volume metastatic castration resistant prostate cancer (mCRPC), but its role in the early treatment of men with only lymph node metastasis (LNM) is unknown. The aim was to assess the outcome of Lu-PSMA RLT earlier in the treatment of men with only LNM. Materials and Methods: Single institution retrospective review of men with only LNM on staging Ga-PSMA PET PSMA who proceeded with Lu-PSMA RLT. Results: There were 17 men with only LNM, including 13 with mCRPC and 3 who were both hormone and chemotherapy naïve. The median PSA was 3.7 (0.46-120 ng/mL). A PSA decline of =50% occurred in 10/17 (58.8%), decreasing to <0.2 ng/mL in 35.3% (6/17). The PSA continues to decline or remain stable in 10/17 (58.8%) with a median follow-up of 13 months, and 8/17 (47.1%) have not reached their pre-treatment levels. There were no significant side effects. There was a better PSA response in men without prior chemotherapy (p=0.05). The prostate cancer specific and overall survival is 82.4% (14/17). Conclusions: Our results identify improved PSA response to Lu-PSMA RLT in men with only LNM, especially in the chemotherapy naïve cohort, compared to previous series with more advanced mCRPC. These findings provide important proof of principle to aid with planning of future prospective randomized trials evaluating the role of Lu-PSMA RLT earlier in the management of node metastatic prostate cancer, including men naïve of ADT and chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract Background For almost a decade, terbium radioisotopes have been explored for their potential theragnostic application in nuclear medicine: 152Tb and 155Tb are the radioisotopes identified for PET or SPECT imaging, while 149Tb and 161Tb have suitable decay characteristics for α- and combined β−/Auger-e−-therapy, respectively. In the present study, the application of 152Tb, in combination with PSMA-617 for imaging of prostate-specific membrane antigen (PSMA)-positive prostate cancer, was demonstrated in a preclinical setting and in a patient with metastatic castration-resistant prostate cancer (mCRPC). Results 152Tb was produced at the ISOLDE facility at CERN/Geneva, Switzerland, by spallation, followed by on-line mass separation. The chemical separation was performed at Paul Scherrer Institute using chromatographic methods, as previously reported. 152Tb was employed for labeling PSMA-617, and the radioligand was extensively investigated in vitro to demonstrate similar characteristics to its 177Lu-labeled counterpart. Preclinical PET/CT imaging studies performed with mice enabled visualization of PSMA-positive PC-3 PIP tumors, while uptake in PSMA-negative PC-3 flu tumors were absent. Based on these promising preclinical results, 152Tb was shipped to Zentralklinik Bad Berka, Germany, where it was used for labeling of PSMA-617, enabling PET imaging of a patient with mCRPC. PET/CT scans were performed over a period of 25 h post injection (p.i.) of the radioligand (140 MBq). The images were of diagnostic quality, particularly those acquired at later time points, and enabled the detection of the same metastatic lesions and of local recurrent tumor as previously detected by 68Ga-PSMA-11 PET/CT acquired 45 min p.i. Conclusions The results of this study demonstrate the successful preparation and preclinical testing of 152Tb-PSMA-617 and its first application in a patient with mCRPC. This work could pave the way towards clinical application of other Tb radionuclides in the near future, most importantly 161Tb, which has promising decay characteristics for an effective treatment of mCRPC patients.

Purpose: Peptide-based prostate-specific membrane antigen (PSMA) targeted radionuclide therapy (TRT) agent [177Lu]-PSMA-617 has emerged as leading TRT candidate for treatment of castration-resistant prostate cancer (mCRPC). [177Lu]-PSMA-617 and other small molecule–based PSMA ligands have shown efficacy in reducing the tumor burden in mCRPC patients but irradiation to the salivary gland and kidneys is a concern and dose-limiting factor. Therefore, methods to reduce non-target organ toxicity are needed to safely treat patients and preserve their quality of life. Herein, we report that addition of cold PSMA ligand PSMA-11 can aid in reducing the uptake of [177Lu]-PSMA-617 in the salivary glands and kidneys. Methods: Groups of athymic nude mice (n = 4) bearing PC3-PIP (PSMA+) tumor xenografts were administered with [177Lu]-PSMA-617 along with 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 and biodistribution studies were performed at 1 h. Results: Biodistribution studies at 1 h post-administration revealed that [177Lu]-PSMA-617 uptake in PC3-PIP tumors was 21.71 ± 6.13, 18.7 ± 2.03, 26.44 ± 2.94, 16.21 ± 3.5, 13.52 ± 3.68, and 12.03 ± 1.96 %ID/g when 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 were added, respectively. Corresponding uptake values in kidney were 123.14 ± 52.52, 132.31 ± 47.4, 84.29 ± 78.25, 2.12 ± 1.88, 1.16 ± 0.36, and 0.64 ± 0.23 %ID/g, respectively. Corresponding salivary gland uptake values were 0.48 ± 0.11, 0.45 ± 0.15, 0.38 ± 0.3, 0.08 ± 0.03, 0.09 ± 0.07, and 0.05 ± 0.02 % ID/g, respectively. Conclusion: The uptake of [177Lu]-PSMA-617 in the salivary gland and kidney can be substantially reduced without significantly impacting tumor uptake by adding cold PSMA-11. [ABSTRACT FROM AUTHOR]

Prostate‐specific membrane antigen (PSMA)‐targeted imaging and therapy of prostate cancer using theranostic pairs is rapidly changing clinical practice. To facilitate clinical trials, fully automated procedures for the radiosyntheses of [68Ga]Ga‐PSMA‐11 and [177Lu]Lu‐PSMA‐617 were developed from commercially available precursors using the cassette based iPHASE MultiSyn module. Formulated and sterile radiopharmaceuticals were obtained in 76 ± 3% (n = 20) and 91 ± 4% (n = 15) radiochemical yields after 17 and 20 min, respectively. Radiochemical purity was always >95% and molar activities exceeded 792 ± 100 and 88 ± 6 GBq/μmol, respectively. Quality control showed conformity with all relevant release criteria and radiopharmaceuticals were used in the clinic. [ABSTRACT FROM AUTHOR]

At present, little is known about the molecular imaging-based response assessment of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with 177Lutetium (177Lu-PSMA-617 RLT) in metastatic castration-resistant prostate cancer (mCRPC). Our study evaluated the response to RLT using both molecular imaging and biochemical response assessments, and their potential prediction of progression-free survival (PFS). Fifty-one consecutive patients given two cycles of RLT at 6-week intervals were analyzed retrospectively. 68Ga-PSMA-11 PET/CT was obtained about 2 weeks prior to the first and 4–6 weeks after the second cycle. Molecular imaging-based response using SUVpeak and tumor-to-liver ratio (TLR) was determined by modified PERCIST criteria. ∆TLR and ∆SUV were significantly correlated with ∆PSA (p < 0.001, each). After a median follow-up of 49 months, the median PFS (95% CI) was 8.0 (5.9–10.1) months. In univariate analysis, responders showing partial remission (PRPSA and PRTLR) had significantly (p < 0.001, each) longer PFS (median: 10.5 and 9.3 months) than non-responders showing either stable or progressive disease (median: 4.0 and 3.5 months). Response assessment using SUVpeak failed to predict survival. In multivariable analysis, response assessment using TLR was independently associated with PFS (p < 0.001), as was good performance status (p = 0.002). Molecular imaging-based response assessment with 68Ga-PSMA-11 PET/CT using normalization of the total lesion PSMA over healthy liver tissue uptake (TLR) could be an appropriate biomarker to monitor RLT in mCRPC patients and to predict progression-free survival (PFS) of this treatment modality.

Background: Prostate-specific membrane antigen (PSMA) is an ideal target for molecular imaging and targeted radionuclide therapy in prostate cancer. Consequently, various PSMA ligands were developed. Some of these molecules are functionalized with a chelator that can host radiometals, such as 68 Ga for PET imaging. The 68 Ga radiolabeling step benefits from process automation, making it more robust and reducing radiation exposure., Objective: To design a single automated radiolabeling protocol for the GMP-compliant preparation of [ 68 Ga]Ga-PSMA-11, transposable to the production of [ 68 Ga]Ga-PSMA-617 and [ 68 Ga]Ga-PSMA-I&T., Methods: A GAIA ® synthesis module and a GALLIAD ® generator were used. Radio-TLC and radio-HPLC methods were validated for radiochemical purity (RCP) determination. Three [ 68 Ga]Ga-PSMA-11 validation batches were produced and thoroughly tested for appearance and pH, radionuclide identity and purity, RCP, stability, residual solvent and sterility. Minimal modifications were made to the reagents and disposables for optimal application to other PSMA ligands., Results: [ 68 Ga]Ga-PSMA-11 for clinical application was produced in 27 min. The 3 validation batches met the quality criteria expected by the European Pharmacopoeia to allow routine production. For optimal transposition to PSMA-617, the solid phase extraction cartridge was changed to improve purification of the radiolabeled product. For application to PSMA-I&T, the buffer solution initially used was replaced by HEPES 2.7 M to achieve good radiochemical yields. Residual HEPES content was checked in the final product and was below the Ph. Eur. threshold., Conclusion: A single automated radiolabeling method on the GAIA ® module was developed and implemented for 68 Ga radiolabeling of 3 PSMA ligands, with slight adjustments for each molecule., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: The main side effect of prostate-specific membrane antigen targeting alpha therapy (PSMA TAT) is dry mouth syndrome. Inflammation of the salivary glands and consequent reduced salivary function have been reported in patients after radioiodine therapy. The beneficial effects of sialendoscopy on radiation-induced inflammation in tissue are well known. Thus sialendoscopy with dilatation, saline irrigation and steroid injections (prednisolone) was performed before and after 225Ac-PSMA-617 TAT to reduce inflammatory effects in the salivary glands and to improve or prevent xerostomia.Methods: Eleven men with metastatic castration-resistant prostate cancer (mean age 68.5 years, range 58-80 years) underwent sialendoscopy, dilatation, saline irrigation and steroid injection of both submandibular and both parotid glands before or after every cycle of 225Ac-PSMA-617 TAT. Sialendoscopy and steroid injection were performed by a senior ENT physician. Quality of life was evaluated using two health-related quality of life (HRQOL) questionnaires, the Xerostomia Questionnaire (XQ) and the Xerostomia Inventory (XI) before and 3 months after the intervention.Results: In all 11 patients both parotid and both submandibular glands were affected by radiation sialadenitis and sialendoscopy was performed. The patients experienced no complications after sialendoscopy, and showed a significant improvement in HRQOL as measured using the XQ and XI. After sialendoscopy the XQ score decreased significantly from 77.7 ± 13.6 to 42.7 ± 14.8 (p = 0.003) and the XI score decreased from 44.5 ± 6.9 to 25.8 ± 12.8 (p = 0.003). Due to the limited number of patients we only report tendencies.Conclusion: Sialendoscopy with dilatation, saline irrigation and steroid injection had beneficial effects on salivary gland function and HRQOL in patients undergoing 225Ac-PSMA-617 RLT. However, even with sialadenoscopic support after multiple cycles of TAT, salivary gland function was reduced and xerostomia was present. Therefore, not only inflammation but also the direct effect of radiation is a putative cause of dry mouth. Further research is necessary to determine the main side effects of PSMA TAT. [ABSTRACT FROM AUTHOR]

Abstract Introduction The widespread clinical utilization of 90Y for preparation of target specific radiopharmaceuticals demands development of a facile, efficient and cost-effective method for radiochemical separation of 90Y from 90Sr via 90Sr/90Y generator. In this article, we describe an efficient and facile method for radiochemical separation of 90Y from 90Sr for preparation of radiopharmaceuticals by exploiting the large difference in the solubility product constants (K sp) of Y(OH) 3 and Sr(OH) 2. Methods A two-step radiochemical separation procedure based on selective precipitation of 90Y under alkaline conditions from 90Sr/90Y equilibrium mixture was developed. The 90Y(OH) 3 colloid formed at pH ~ 10 was selectively trapped in 0.22 μm sterile filter and was subsequently retrieved by dissolution in HCl solution. Detailed quality control analyses of obtained 90Y were carried out and its utility towards preparation of different radiopharmaceuticals was assessed. Results Using the same feed solution of 90Sr (3.7 GBq), consistent and repeated separation of 90Y could be achieved in different batches with >85% yield and >99.999% radionuclidic purity. Yttrium-90 obtained from this process was found suitable for preparation of therapeutically relevant doses of three different radiopharmaceutical formulations, namely, 90Y-DOTA-TATE, 90Y-PSMA-617 and 90Y-CHX-A″-DTPA-Cetuximab with >95% radiochemical purity. Conclusions The promising results obtained in this study would facilitate implementation of the developed technique for obtaining 90Y in adequate quantity and of required purity from a centralized radiopharmacy setup. [ABSTRACT FROM AUTHOR]

Lutetium-177-labeled PSMA inhibitor has emerged as a promising modality for targeted therapy of prostate carcinoma. A protocol for regular multidose formulation of ready-to-use 177 Lu-PSMA-617 has been developed based on detailed and systematic radiochemical investigations. The formulation meets the requirements of clinical use and can be shipped to nuclear medicine centres for administration up to 4 days from the date of formulation. The reported protocol would be useful toward facilitating widespread clinical utilization of 177 Lu-PSMA-617 in the management of prostate cancer. [ABSTRACT FROM AUTHOR]