Prostate-specific Membrane Antigen Ligand Research Articles

Advances in PSMA theranostics

The validation of prostate specific membrane antigen (PSMA) as a molecular target in metastatic castration-resistant prostate cancer has stimulated the development of multiple classes of theranostic ligands that specifically target PSMA. Theranostic ligands are used to image disease or selectively deliver cytotoxic radioactivity to cells expressing PSMA according to the radioisotope conjugated to the ligand. PSMA theranostics is a rapidly advancing field that is now integrating into clinical management of prostate cancer patients. In this review we summarize published research describing the biological role(s) and activity of PSMA, highlight the most clinically advanced PSMA targeting molecules and biomacromolecules, and identify next generation PSMA ligands that aim to further improve treatment efficacy. The goal of this review is to provide a comprehensive assessment of the current state-of-play and a roadmap to achieving further advances in PSMA theranostics.

Clinical Pharmacology of Radiotheranostics in Oncology.

The combined use of diagnostic and therapeutic radioligands with the same molecular target, also known as theranostics, enables accurate patient selection, targeted therapy, and prediction of treatment response. Radioiodine, bone-seeking radioligands and norepinephrine analogs have been used for many years for diagnostic imaging and radioligand therapy of thyroid carcinoma, bone metastases, pheochromocytoma, paraganglioma, and neuroblastoma, respectively. In recent years, radiolabeled somatostatin analogs and prostate-specific membrane antigen ligands have shown clinical efficacy in the treatment of neuroendocrine tumors and prostate cancer, respectively. Several candidate compounds are targeting novel theranostic targets such as fibroblast activation protein, C-X-C chemokine receptor 4, and gastrin-releasing peptide receptor. In addition, several strategies to improve efficacy of radioligand therapy are being evaluated, including dosimetry-based dose optimization, multireceptor targeting, upregulation of target receptors, radiosensitization, pharmacogenomics, and radiation genomics. Design and evaluation of novel radioligands and optimization of dose and dose schedules, within the complex context of individualized multimodal cancer treatment, requires a multidisciplinary approach that includes clinical pharmacology. Significant increases in the use of these radiopharmaceuticals in routine oncological practice can be expected, which will have major impact on patient care as well as (radio)pharmacy utilization.

Feasibility and Optimal Time Point of [68Ga]Gallium-labeled Prostate-specific Membrane Antigen Ligand Positron Emission Tomography Imaging in Patients Undergoing Cytoreductive Surgery After Systemic Therapy for Primary Oligometastatic Prostate Cancer: Implications for Patient Selection and Extent of Surgery

BackgroundProstate-specific membrane antigen (PSMA) targeted molecular imaging using positron emission tomography (PET) has significantly improved the diagnosis and treatment of prostate cancer (PCA). ObjectiveTo assess the feasibility and compare the diagnostic accuracy of [68Ga]Ga-PSMA-11 PET images taken at baseline, before the initiation of systemic treatment and preoperative images, using histopathology after cytoreductive surgery as reference. Design, setting, and participantsWe identified 20 patients in our prospectively maintained database with primary oligometastatic PCA who underwent cytoreductive radical prostatectomy and superextended pelvic lymph node dissection after systemic therapy, who had baseline and preoperative [68Ga]Ga-PSMA-11 PET imaging available. Outcome measurements and statistical analysisWe performed a region-based analysis to determine the diagnostic accuracy of imaging, using pathology as a reference. Regions were predefined as prostate, internal iliac left/right, obturator left/right, external iliac left/right, common iliac left/right, and presacral. Results and limitationsSensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and diagnostic effectiveness were, respectively, 95.65%, 78.22%, 98.39%, 57.89%, and 83.00% for baseline [68Ga]Ga-PSMA-11 PET, compared to 56.52%, 98.05%, 88.30%, 89.66%, and 88.50% for preoperative [68Ga]Ga-PSMA-11 PET. On a receiver operating characteristic analysis, the diagnostic accuracy of baseline [68Ga]Ga-PSMA-11 PET with an area under the curve (AUC) of 0.87 (95% confidence interval [CI] 0.83–0.92) was significantly better than that of preoperative [68Ga]Ga-PSMA-11 PET after systemic therapy with an AUC of 0.77 (95% CI 0.70–0.85, p = 0.01). ConclusionsBaseline imaging, [68Ga]Ga-PSMA-11 PET has significantly better diagnostic accuracy, sensitivity, and NPV than images obtained preoperatively, in systemically pretreated patients. If a patient is suitable for local treatment and complete resection of the residual tumor is intended, [68Ga]Ga-PSMA-11 PET images taken prior to systemic therapy are significantly more accurate in selecting the relevant lymph nodes for resection. Patient summaryWe found that prostate-specific membrane antigen positron emission tomography (PSMA-PET) imaging used early, before hormonal therapy or chemotherapy, provides more accurate information about the spread of the disease, than if used immediately before surgery but after hormonal therapy or chemotherapy. Early use of PSMA-PET has the potential to improve therapy also at later stages of the disease.

A Preliminary Study of PSMA Fluorescent Probe for Targeted Fluorescence Imaging of Prostate Cancer.

Purpose: With the increasing detection rate of early prostate cancer (PCa), the proportion of surgical treatment is increasing. Surgery is the most effective treatment for PCa. Precise targeting of tumors during surgery can reduce the incidence of positive surgical margins (PSMs) and preserve the neurovascular bundles (NVBs) as much as possible. The objective of this study was to synthesize a PSMA fluorescent probe (PSMA-Cy5) and verify the targeting specificity of the probe for prostate cancer, thereby providing a theoretical basis for the development of PSMA fluorescent probes for clinical application in the future. Methods: In this study, a novel water-soluble 3H-indocyanine-type bioluminescent dye-Cy5-labeled prostate-specific membrane antigen (PSMA) ligand (PSMA-Cy5) was synthesized by liquid phase synthesis. The PSMA ligand was developed based on the glutamine-urea-lysine (Glu-urea-Lys) structure. The new fluorescent probe was evaluated in vitro and in vivo, and its safety was evaluated. Confocal microscopy was used to observe the binding uptake of PSMA-Cy5 with PSMA (+) LNCaP cells, PSMA (-) PC3 cells and blocked LNCaP cells. In in vivo optical imaging studies, the targeting specificity of PSMA (+) 22Rv1 tumors to probe binding was validated by tail vein injection of PSMA-Cy5. The safety of the PSMA-Cy5 probe was evaluated by histopathological analysis of mouse organs by a single high-dose tail vein injection of PSMA-Cy5. Results: In vitro fluorescence cell uptake experiments showed that the binding of PSMA-Cy5 to LNCaP cells has targeting specificity. PC3 cells and blocked LNCaP cells showed almost no uptake. The results of in vivo optical imaging studies showed that the tumor-to-background ratio in the 22Rv1 group was 3.39 ± 0.47; in the 22Rv1 blocking group it was 0.78 ± 0.15, and in the PC3 group it was 0.94 ± 0.09, consistent with the in vitro results. After a high-dose injection of PSMA-Cy5, there were no abnormalities in the tissues or organs of the mice. The probe showed good safety. Conclusions: PSMA-Cy5 is a probe with good targeting specificity and low toxicity that can accurately visualize tumors in vivo. This study has an important reference value for the development of PSMA fluorescent probes. In the future, it can be applied to precise tumor imaging during radical prostatectomy to reduce the incidence of postoperative PSM.

Self-Assembled PSMA-Targeted Nanoparticles Enhanced Photodynamic Therapy in Prostate Cancer

Prostate cancer greatly threatens human health. Many treatment strategies including surgery and radiotherapy are applied to treat prostate cancer. However, these treatment strategies will bring great side effects. Herein, we developed a functionalized Prostate-Specific Membrane Antigen-Chlorin e6 (PSMA-Ce6) NPs to enhance photodynamic therapy to reduce the side effects of prostate cancer treatments. We linked the hydrophobic photosensitizer Ce6 with the small hydrophilic molecule PSMA ligand through a covalent bond to form a functionalized PSMA-Ce6. In aqueous phase, the PSMA-Ce6 self-assembled into nanoparticles with a hydrophobic core and a hydrophilic shell, which significantly enhanced the accumulation of PSMA-Ce6 in the tumor. The molecularly targeted drug PSMA inhibitor can not only specifically inhibit PSMA but also increase the accumulation of the photosensitizer Ce6 in the tumor and achieve a completed tumor ablation under the near infrared (NIR) irradiation. PSMA-Ce6 NPs have great potential for translation into clinical applications.

How Image-Guided Pathology Can Improve the Detection of Lymph Node Metastases in Prostate Cancer.

Detection of lymph node (LN) metastases in prostate cancer (PCa) is pivotal for accurate staging and determining treatment options. To date, the reference standard for nodal staging is histopathological examination of all harvested surgical specimens from extended pelvic LN dissections. However, this is a labor-intensive process, and small metastatic foci can be missed due to sampling effects. With current research expanding toward using radiolabeled prostate-specific membrane antigen ligands for image-guided surgery, new opportunities arise for image-guided pathological assessment of surgical specimens. Here, we illustrate how molecular imaging can complement histopathology and improve accurate detection of LN metastases.

Management of Patients with Advanced Prostate Cancer: Report from the Advanced Prostate Cancer Consensus Conference 2021

BackgroundInnovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but various areas of management still lack high-level evidence to inform clinical practice. The 2021 Advanced Prostate Cancer Consensus Conference (APCCC) addressed some of these questions to supplement guidelines that are based on level 1 evidence. ObjectiveTo present the voting results from APCCC 2021. Design, setting, and participantsThe experts identified three major areas of controversy related to management of advanced prostate cancer: newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), the use of prostate-specific membrane antigen ligands in diagnostics and therapy, and molecular characterisation of tissue and blood. A panel of 86 international prostate cancer experts developed the programme and the consensus questions. Outcome measurements and statistical analysisThe panel voted publicly but anonymously on 107 pre-defined questions, which were developed by both voting and non-voting panel members prior to the conference following a modified Delphi process. Results and limitationsThe voting reflected the opinions of panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results reported in the Supplementary material. ConclusionsThese voting results from a panel of experts in advanced prostate cancer can help clinicians and patients to navigate controversial areas of management for which high-level evidence is scant. However, diagnostic and treatment decisions should always be individualised according to patient characteristics, such as the extent and location of disease, prior treatment(s), comorbidities, patient preferences, and treatment recommendations, and should also incorporate current and emerging clinical evidence and logistic and economic constraints. Enrolment in clinical trials should be strongly encouraged. Importantly, APCCC 2021 once again identified salient questions that merit evaluation in specifically designed trials. Patient summaryThe Advanced Prostate Cancer Consensus Conference is a forum for discussing current diagnosis and treatment options for patients with advanced prostate cancer. An expert panel votes on predefined questions focused on the most clinically relevant areas for treatment of advanced prostate cancer for which there are gaps in knowledge. The voting results provide a practical guide to help clinicians in discussing treatment options with patients as part of shared decision-making.

The Diagnostic Performance of 18F-PSMA-1007 PET/CT in Prostate Cancer Patients with Early Recurrence after Definitive Therapy with a PSA

The prostate bed is one of the common sites of early recurrence of prostate cancer. The currently used PSMA ligands (68Ga-PSMA-11 and 99mTc-PSMA) undergo early urinary clearance resulting in interfering physiological activity within and surrounding the prostate. This can result in sites of cancer recurrence being obscured. 18F-PSMA-1007 has an advantage of delayed urinary clearance thus the prostate region is reviewed without any interfering physiological activity. The aim of this study was to determine the diagnostic performance of 18F-PSMA-1007 PET/CT in patients with early biochemical recurrence after definitive therapy. Forty-six Prostate cancer (mean age 66.7±7.5, range 48-87 years) presenting with biochemical recurrence (median PSA 1.6ng/ml, range 0.1-10.0) underwent non-contrast-enhanced 18F-PSMA-1007 PET/CT. PET/CT findings were evaluated qualitatively and semiquantitatively (SUVmax) and compared to the results of histology, Gleason grade, and conventional imaging. Twenty-four of the 46 (52.2%) patients demonstrated a site of recurrence on 18F-PSMA-1007 PET/CT. Oligometastatic disease was detected in 15 (32.6%) of these patients. Of these 10 (37.5%) demonstrated intra-prostatic recurrence, lymph node disease was noted in 11 (45.8%) whilst two patients demonstrated skeletal metastases. The detection rates for PSA levels 0-<0.5, 0.5-<1, 1-2, >2 were 31.3%, 33.3%, 55.6% and 72.2% respectively. 7 (29.2%) of the positive patients had been described as negative or equivocal on conventional imaging. An optimal PSA cut-off level of 1.3ng/ml was found. 18F-PSMA-1007 demonstrated good diagnostic performance detecting sites of recurrence. Its ability to detect sites of recurrence in the setting of early biochemical recurrence will have a significant impact on patient management.

Preliminary Evaluation of 68Ga-P16-093, a PET Radiotracer Targeting Prostate-Specific Membrane Antigen in Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is a promising molecular target for imaging of prostate adenocarcinoma. 68Ga-P16-093, a small molecule PSMA ligand, previously showed equivalent diagnostic performance compared to 68Ga-PSMA-11 PET/CT in a pilot study of prostate cancer patients with biochemical recurrence (BCR). We performed a pilot study for further characterization of 68Ga-P16-093 including comparison to conventional imaging. Patients were enrolled into two cohorts. The biodistribution cohort included 8 treated prostate cancer patients without recurrence, who underwent 6 whole body PET/CT scans with urine sampling for dosimetry using OLINDA/EXM. The dynamic cohort included 15 patients with BCR and 2 patients with primary prostate cancer. Two patients with renal cell carcinoma were also enrolled for exploratory use. A dynamic PET/CT was followed by 2 whole body scans for imaging protocol optimization based on bootstrapped replicates. 68Ga-P16-093 PET/CT was compared for diagnostic performance against available 18F-fluciclovine PET/CT, 99mTc-MDP scintigraphy, diagnostic CT, and MRI. 68Ga-P16-093 deposited similar effective dose (0.024mSv/MBq) and lower urinary bladder dose (0.064mSv/MBq) compared to 68Ga-PSMA-11. The kidneys were the critical organ (0.290mSv/MBq). While higher injected activities were preferable, lower injected activities at 74-111MBq (2-3mCi) yielded 80% retention in signal-to-noise ratio. The optimal injection-to-scan interval was 60min, with acceptable delay up to 90min. 68Ga-P16-093 PET/CT showed superior diagnostic performance over conventional imaging with overall patient-level lesion detection rate of 71%, leading to a change in management in 42% of the patients. Based on its favorable imaging characteristics and diagnostic performance in prostate cancer, 68Ga-P16-093 PET/CT merits further investigation in larger clinical studies.

Stereotactic Radiotherapy for Lesions Detected via 68Ga-Prostate-specific Membrane Antigen and 18F-Fluorodexyglucose Positron Emission Tomography/Computed Tomography in Patients with Nonmetastatic Prostate Cancer with Early Prostate-specific Antigen Progression on Androgen Deprivation Therapy: A Prospective Single-center Study

BackgroundDual-tracer positron emission tomography/computed tomography (PET/CT) with a 68Ga-labelled prostate-specific membrane antigen (PSMA) ligand and 18F-fluorodeoxyglucose (FDG) improves detection of metastatic heterogeneity and burden in patients with nonmetastatic prostate cancer (nmPCa). However, there is limited prospective evidence regarding its impact on the efficacy of stereotactic body radiotherapy (SBRT). ObjectiveTo evaluate metastasis-free survival (MFS) and toxicity after SBRT to dual-tracer PET/CT-detected metastases in patients with nmPCa and early prostate-specific antigen (PSA) progression on androgen deprivation therapy (ADT; PSA ≤2 ng/ml). Design, setting, and participantsPatients were prospectively screened using dual-tracer PET/CT between April 2019 and October 2020. SBRT was recommended for patients with five or fewer nonvisceral metastases (SBRT group). Patients without detectable metastases (N−/M− group) and those who refused SBRT (ADT group) continued to receive ADT. Patients were followed with conventional imaging. InterventionSBRT to each PET/CT-detected metastasis. Outcome measurements and statistical analysisKaplan-Meier methods were used to determine MFS. Toxicity was evaluated using Common Terminology Criteria for Adverse Event v4.0. Results and limitationsSeventy-four consecutive patients were screened. The median PSA and PSA doubling time were 0.59 ng/ml and 4.56 mo, respectively. Overall, 54 patients had metastases and 17 had PSMA-/FDG+ disease. Seven patients were excluded from the MFS analysis, including two with a history of abiraterone treatment and five with more than five metastases. The median follow-up was 21.4 mo. The ADT group had shorter MFS than the SBRT group (11.0 mo vs not reached; hazard ratio [HR] 4.69, 95% confidence interval [CI] 2.92–25.0; p < 0.001) and the N−/M− group (11.0 mo vs not reached; HR 8.78, 95% CI 4.04–40.30; p < 0.001). There was no significant difference in median MFS between the SBRT group and the N−/M− group (p = 0.261). A PSA response >90% was achieved by 86% of patients in the SBRT group. There were no grade ≥3 adverse events after SBRT. The nonrandomized design is the major study limitation. ConclusionsDual-tracer PET/CT-guided SBRT delivered superior local control rates in comparison to ADT alone and had minimal toxicity. Patient summaryWe investigated metastasis-targeted radiotherapy for patients with up to five prostate cancer metastases detected with two different radioisotope scans. Our results show that this approach yields promising metastasis-free survival and low toxicity.

18F-rhPSMA-7 PET for the Detection of Biochemical Recurrence of Prostate Cancer After Curative-Intent Radiation Therapy: A Bicentric Retrospective Study.

This bicentric, retrospective analysis investigated the efficacy of PET/CT with a novel theranostic prostate-specific membrane antigen (PSMA)--targeting ligand, 18F-rhPSMA-7, in patients with biochemical recurrence (BCR) of prostate cancer after curative-intent primary radiotherapy. Methods: Datasets from patients with BCR of prostate cancer after external-beam radiation therapy or brachytherapy who underwent 18F-rhPSMA-7 PET/CT at either Technical University Munich or Ludwig-Maximilians-University Munich were retrospectively reviewed by experienced nuclear medicine physicians and radiologists at both centers. The median injected activity was 299 MBq (range, 204-420 MBq), and the median uptake time was 77 min (range, 46-120 min). All lesions suggestive of recurrent prostate cancer were noted. Detection rates were correlated with patients' prostate-specific antigen (PSA) level, primary Gleason score, and prior use of androgen-deprivation therapy (ADT). Results: Ninety-seven patients were included (65 at Technical University Munich and 32 at Ludwig-Maximilians-University Munich). The median prescan PSA was 4.19 ng/mL (range, 0.1-159 ng/mL). The primary Gleason score was ≤6 in 19 patients, 7 in 25, ≥8 in 33, and unknown in 20. Thirty patients received ADT in the 6 mo preceding PET/CT. 18F-rhPSMA-7 identified lesions in 91 of 97 (94%) patients. Detection rates stratified by PSA were 88% (22/25), 97% (30/31), 90% (19/21), and 100% (20/20) for a PSA of <2, 2-<5, 5-<10, and ≥10 ng/mL, respectively. Detection rates in the subgroup of patients not meeting the Phoenix criteria for BCR were 80% (4/5), 90% (9/10), 100% (4/4), and 83% (5/6) for a PSA of <0.5, 0.5-<1, 1-<1.5, and 1.5-2 ng/mL, respectively. There were no significant differences in detection rates between patients with and without prior ADT (100% vs. 91%, P = 0.173) or patients with a Gleason score of ≤7 and a Gleason score of ≥8 (98% vs. 91%, P = 0.316).18F-rhPSMA-7 revealed local recurrence in 80% (78/97); pelvic lymph node metastases in 38% (37/97); retroperitoneal and supradiaphragmatic lymph node metastases in 9% (9/97) and 4% (4/97), respectively; bone metastases in 27% (26/97); and visceral metastases in 3% (3/97). In the subgroup of patients with a PSA of <2 ng/mL above nadir, local recurrence occurred in 76% (19/25) and pelvic lymph node metastases in 36% (9/25). Conclusion:18F-rhPSMA-7 PET/CT demonstrates high detection rates in prostate cancer patients with BCR after primary radiation therapy, even at low PSA values. Its diagnostic efficacy is comparable to published data for other PSMA ligands.

Robot-Assisted Prostate-Specific Membrane Antigen-Radioguided Surgery in Primary Diagnosed Prostate Cancer.

The objective of this study was to evaluate the safety and feasibility of 99mTc-based prostate-specific membrane antigen (PSMA) robot-assisted-radioguided surgery to aid or improve the intraoperative detection of lymph node metastases during primary robot-assisted radical prostatectomy (RARP) for prostate cancer (PCa). Methods: Men with primary high-risk PCa (≥ cT3a, International Society of Urological Pathology (ISUP) grade group ≥ 3 or prostate-specific antigen of ≥ 15 ng/mL) with potential lymph node metastasis (Briganti nomogram risk > 10% or on preoperative imaging) were enrolled in the study. Patients underwent staging 68Ga-PSMA PET/CT scanning. Preoperatively, a 99mTc-labeled PSMA ligand (99mTc PSMA I&S; 500 MBq) was administered followed by SPECT/CT. A RARP including extended pelvic lymph node dissection was performed, with intraoperative tracing of PSMA-avid tissues using a prototype DROP-IN γ-probe. Resected specimens were also measured ex vivo. Histopathologic concordance with probe findings was evaluated. A radiotracer count of ≥ 1.5 times the background reference (invivo), and ≥ 10 (absolute count) in the ex vivo setting, was considered positive. Results: Twelve patients were included (median age, 68 y, and prostate-specific antigen, 9.15 ng/mL). Most of the patients harbored ISUP 5 PCa (75%) and had avid lymph nodes on preoperative PSMA PET (64%). The DROP-IN probe aided resection of PSMA-avid (out-of-template) lymph nodes and residual disease at the prostate bed. Eleven metastatic lymph nodes were identified by the probe that were not observed on preoperative 68Ga-PSMA PET/CT. Of the 74 extraprostatic tissue specimens that were resected, 22 (29.7%) contained PCa. The sensitivity, specificity, positive predictive value, and negative predictive value of inpatient use of the γ-probe were 76% (95% CI, 53%-92%), 69% (95% CI, 55%-81%), 50%, and 88%, respectively. Ex vivo, the diagnostic accuracy was superior: 76% (95% CI, 53%-92%), 96% (95% CI, 87%-99%), 89%, and 91%, respectively, for sensitivity, specificity, positive predictive value, and negative predictive value. Of the missed lymph nodes invivo (n = 5) and ex vivo (n = 5), 90% were micrometastasis (≤3 mm). No complications greater than Clavien-Dindo Grade I occurred. Conclusion: Robot-assisted 99mTc-based PSMA-radioguided surgery is feasible and safe in the primary setting, optimizing the detection of nodal metastases at the time of RARP and extended pelvic lymph node dissection. Further improvement of the detector technology may optimize the capabilities of robot-assisted 99mTc-based PSMA-radioguided surgery.

Temporary Reactive Response of Axillary Lymph Nodes to COVID-19 Vaccination on 18F-rhPSMA-7.3 PET/CT in Patients with Prostate Cancer.

Vaccine-associated lymphadenopathy (VAL) is a common finding on 18F-FDG PET/CT examinations after coronavirus disease 2019 (COVID-19) vaccination. However, data regarding VAL on 18F-rhPSMA-7.3-ligand PET are currently lacking. This study assesses the prevalence, temporal response to vaccination, and characteristics of VAL. Methods: Two hundred thirty-three consecutive vaccinated and 41 unvaccinated patients with confirmed prostate cancer who underwent 18F-rhPSMA-7.3 PET/CT were retrospectively analyzed. Size and uptake of the axillary lymph nodes were measured. Ratios of SUVmax of ipsilateral to contralateral axillary lymph node (SUVratio) were determined. The characteristics of SUVratio in respect to the duration of PSMA avidity in the axillary lymph node after COVID-19 vaccination was analyzed. Results: The prevalence of VAL on 18F-rhPSMA-7.3 PET was 45%. Up to a period of 8 wk after the last COVID-19 vaccination, SUVratio was positive (2.05 ± 0.17). Thereafter, SUVratio dropped significantly (1.35 ± 0.09) and approached the value of unvaccinated group (1.1 ± 0.2). SUVratio of metastatic axillary lymph nodes was very high (>11) and can be easily detected visually or semiquantitatively. In 3 patients, we observed suspected development and consecutively confirmed involving metastasis of axillary lymph node with SUVratio between 4.0 to 6.6. Correlation between SUVratio and lymph node size (r = 0.93, P < 0.0001) and lymph node size and duration after vaccine (r = -0.88, P < 0.0008) was found. Conclusion: Increased uptake of the PSMA ligand 18F-rhPSMA-7.3 by axillary lymph nodes is common after COVID-19 vaccination and can persist for 8 wk. This finding should be considered in the interpretation of 18F-rhPSMA-7.3 PET/CT examinations.

Synthesis of a new bifunctional NODA for bioconjugation with PSMA ligand and one-step Al18F labeling

The Al18F labeling method is a relatively new approach that allows radiofluorination of biomolecules such as peptides and proteins in a one-step procedure and in an aqueous solution. However, instability of the complex of [AlF]2+ with hexadentate chelator NOTA may attribute to the disassociation of free 18F− and [Al18F]2+ and accumulation in bone. In this study, we designed and synthesized a new bifunctional pentadentate AlF-chelator p-SCN-PhPr-NODA as well as its nitro form p-NO2-PhPr-NODA. Chelator p-NO2-PhPr-NODA exhibited increased Al (III) complexation kinetics determined by AA III complexation kinetic studies and stronger coordination ability towards [AlF]2+ according to DFT calculation studies in comparison with hexadentate chelator NOTA. As a proof of concept, bifunctional chelator p-SCN-PhPr-NODA was furthermore conjugated to a PSMA targeting moiety Glu-urea-Lys to form NODA-PrPh-GuL. The conjugated peptide showed acceptable radiochemical yield (12.5–16.4%) and efficiency with an excellent radiochemical purity (∼100% after SPE purification) in Al18F labeling. The labeled peptide exhibited good in vitro stability and significant specificity for PSMA. Biodistribution study and MicroPET scan in healthy Kun Ming mice with the labeled peptide were performed and demonstrated excellent in vivo stability of Al18F-labeled construct. In general, the successful application of the new bifunctional chelator in labeling dipeptide Glu-urea-Lys with Al18F could facilitate its possibility in conjugating with other peptides for PET imaging with enhanced in vivo stability, thus providing better in vivo performances.

Modern possibilities of application &lt;sup&gt;99m&lt;/sup&gt;Tc-labeled prostate-specific membrane antigen ligands in prostate cancer

This article presents a modern possibilities and future path of prostate-specific membrane antigen (PSMA) radiopharmacuticals labeled by 99mTc, that is the most popular isotope using in conventional nuclear medicine. The main advantages and disadvantages of SPECT/CT with these radiopharmaceuticals in different phases of prostate cancer continuum have been analyzed. Results of research diagnostic sensitivity of 99mTc-PSMA SPECT/CT including comparison with 68Ga-PSMA PET/CT and conventional modality such as MRI and bone scan are presented. The prerequisites of application 99mTc-labeled PSMA ligands in PSMA-guided surgery, methodology of PSMA-guided surgery and foreign authors application experience are presented in this article too.

Cold Kit Labeling: The Future of 68Ga Radiopharmaceuticals?

Over the last couple of decades, gallium-68 (68Ga) has gained a formidable interest for PET molecular imaging of various conditions, from cancer to infection, through cardiac pathologies or neuropathies. It has gained routine use, with successful radiopharmaceuticals such as somatostatin analogs ([68Ga]Ga-DOTATOC and [68Ga]GaDOTATATE) for neuroendocrine tumors, and PSMA ligands for prostate cancer. It represents a major clinical impact, particularly in the context of theranostics, coupled with their 177Lu-labeled counterparts. Beside those, a bunch of new 68Ga-labeled molecules are in the preclinical and clinical pipelines, with some of them showing great promise for patient care. Increasing clinical demand and regulatory issues have led to the development of automated procedures for the production of 68Ga radiopharmaceuticals. However, the widespread use of these radiopharmaceuticals may rely on simple and efficient radiolabeling methods, undemanding in terms of equipment and infrastructure. To make them technically and economically accessible to the medical community and its patients, it appears mandatory to develop a procedure similar to the well-established kit-based 99mTc chemistry. Already available commercial kits for the production of 68Ga radiopharmaceuticals have demonstrated the feasibility of using such an approach, thus paving the way for more kit-based 68Ga radiopharmaceuticals to be developed. This article discusses the development of 68Ga cold kit radiopharmacy, including technical issues, and regulatory aspects.

Preclinical biodistribution and dosimetry and human biodistribution comparing 18F-rhPSMA-7 and single isomer 18F-rhPSMA-7.3

BackgroundRadiohybrid prostate-specific membrane antigen (rhPSMA) ligands such as 18F-rhPSMA-7 are a new class of theranostic agents in clinical development for prostate cancer. We compared preclinical dosimetry and human biodistribution of 18F-rhPSMA-7 with that of single diastereoisomer form, 18F-rhPSMA-7.3.MethodsPreclinical dosimetry was performed with SCID-mice sacrificed at multiple timepoints (10–300 min) post-injection of 25.6 ± 3.6 MBq 18F-rhPSMA-7 or 28.5 ± 4.8 MBq 18F-rhPSMA-7.3 (n = 3–6 mice per timepoint). Heart, lung, liver, spleen, pancreas, fat, stomach, small intestine, large intestine, kidney, muscle, bone, bladder, testicles, tail, and brain tissue were harvested, and urine and blood samples collected. Percentage of injected dose per gram was calculated. Absorbed doses were estimated with OLINDA/EXM 1.0.18F-rhPSMA-7 (n = 47) and 18F-rhPSMA-7.3 (n = 33) PET/CT exams were used to estimate human biodistribution. Mean (range) injected activities were 324 (236–424) MBq versus 345 (235–420) MBq, and acquisition times were 84 (42–166) versus 76 (59–122) minutes for 18F-rhPSMA-7 versus 18F-rhPSMA-7.3, respectively. SUVmean was determined for background (gluteal muscle), normal organs (salivary glands, blood pool, lung, liver, spleen, pancreas, duodenum, kidney, bladder, bone) and up to three representative tumour lesions. Qualitative analyses assessed image quality, non-specific blood pool activity, and background uptake in bone/marrow using 3/4-point scales.ResultsPreclinical dosimetry revealed that at 3.5 h and 1 h bladder voiding intervals, the extrapolated total effective doses were 26.6 and 12.2 µSv/MBq for 18F-rhPSMA-7 and 21.7 and 12.8 µSv/MBq for 18F-rhPSMA-7.3 respectively.Human biodistribution of both agents was typical of other PSMA-ligands and broadly similar to each other; SUVmean were 16.9 versus 16.2 (parotid gland), 19.6 versus 19.9 (submandibular gland), 2.0 versus 1.9 (blood pool, p < 0.005), 0.7 versus 0.7 (lungs), 7.0 versus 7.3 (liver), 9.1 versus 8.4 (spleen), 32.4 versus 35.7 (kidney), 2.5 versus 2.8 (pancreas), 10.9 versus 11.0 (duodenum), 1.1 versus 1.3 (bone) and 4.6 versus 2.0 (bladder; p < 0.001) for 18F-rhPSMA-7 versus 18F-rhPSMA-7.3, respectively. Tumour SUVmean was higher for 18F-rhPSMA-7.3 (32.5 ± 42.7, n = 63 lesions) than for 18F-rhPSMA-7 (20.0 ± 20.2, n = 89 lesions).ConclusionsRadiation dosimetry is favourable for both agents. Radiation exposure, assuming a 1 h voiding interval, is less than 5 mSv after injection of 370 MBq. 18F-rhPSMA-7.3 showed significantly lower bladder uptake, and a higher uptake trend in tumours compared with 18F-rhPSMA-7.

68Ga-PSMA-11 uptake in tracheal mucus plug - a potential pitfall.

Prostate-specific membrane antigen (PSMA) PET/CT is a well-acclaimed imaging modality for prostate cancer (PCa). However, many reports have highlighted PSMA radioligand uptake in a variety of benign tumors and lesions. We report a case of PCa in which 68Ga-PSMA-11 uptake was noted in the tracheal lumen. However, 18F-PSMA-1007 PET/CT was done on a subsequent day, which demonstrated no abnormal radiotracer uptake or morphological lesion within the tracheal lumen. This case highlights an uncommon finding of PSMA ligand uptake in a tracheal mucus plug (non-prostatic benign uptake), which may be misinterpreted as a false-positive finding.

Hematotoxicity and Nephrotoxicity in Prostate Cancer Patients Undergoing Radioligand Therapy with [177Lu]Lu-PSMA I&T.

Simple SummaryRadioligand therapy (RLT) with prostate-specific membrane antigen (PSMA)-directed agents has shown remarkable results in patients with advanced prostate cancer. Our objective was to provide data on the side effect profile of PSMA-directed RLT using the therapeutic radiotracer [177Lu]Lu-PSMA I&T. We evaluated patients with castration-resistant metastatic prostate cancer treated with at least three cycles of [177Lu]Lu-PSMA I&T. A substantial fraction of the patients already had impaired renal function and/or reduced white blood cell counts at baseline, but the degree of nephrotoxicity or hematotoxicity under RLT was low. No severe toxicities occurred under RLT.(1) Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) has shown remarkable results in patients with advanced prostate cancer. We aimed to evaluate the toxicity profile of the PSMA ligand [177Lu]Lu-PSMA I&T. (2) Methods: 49 patients with metastatic, castration-resistant prostate cancer treated with at least three cycles of [177Lu]Lu-PSMA I&T were evaluated. Prior to and after RLT, we compared leukocytes, hemoglobin, platelet counts, and renal functional parameters (creatinine, eGFR, n = 49; [99mTc]-MAG3-derived tubular extraction rate (TER), n = 42). Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and KDIGO Society. To identify predictive factors, we used Spearman’s rank correlation coefficient. (3) Results: A substantial fraction of the patients already showed impaired renal function and reduced leukocyte counts at baseline. Under RLT, 11/49 (22%) patients presented with nephrotoxicity CTCAE I or II according to creatinine, but 33/49 (67%) according to eGFR. Only 5/42 (13%) showed reduced TER, defined as <70% of the age-adjusted mean normal values. Of all renal functional parameters, absolute changes of only 2% were recorded. CTCAE-based re-categorization was infrequent, with creatinine worsening from I to II in 2/49 (4.1%; GFR, 1/49 (2%)). Similar results were recorded for KDIGO (G2 to G3a, 1/49 (2%); G3a to G3b, 2/49 (4.1%)). After three cycles, follow-up eGFR correlated negatively with age (r = −0.40, p = 0.005) and the eGFR change with Gleason score (r = −0.35, p < 0.05) at baseline. Leukocytopenia CTCAE II occurred only in 1/49 (2%) (CTCAE I, 20/49 (41%)) and CTCAE I thrombocytopenia in 7/49 (14%), with an absolute decrease of 15.2% and 16.6% for leukocyte and platelet counts. Anemia CTCAE II occurred in 10/49 (20%) (CTCAE I, 36/49 (73%)) with a decrease in hemoglobin of 4.7%. (4) Conclusions: After PSMA-targeted therapy using [177Lu]Lu-PSMA I&T, no severe (CTCAE III/IV) toxicities occurred, thereby demonstrating that serious adverse renal or hematological events are unlikely to be a frequent phenomenon with this agent.

68Ga-PSMA PET/CT Scan Leading to Diagnosis of PSMA-Positive Rectal Adenocarcinoma in a Patient With Prostate Cancer.

A 59-year-old prostate cancer patient, status post radical prostatectomy, was referred to our department for restaging with 68Ga-prostate-specific membrane antigen (PSMA) PET/CT scan. Aside multiple metastatic lesions involving pelvic lymph nodes as well as the right femoral trochanter, a PSMA-positive rectal wall thickening was detected. Colonoscopy correlation and tissue diagnosis, recommended to rule out accompanying primary malignancy, confirmed the presence of rectal adenocarcinoma. This case signifies the importance of requesting pathological correlation for unexplained PSMA-positive lesions, emphasizing the potential role PSMA ligands may play in detecting occult second primary malignancies, especially synchronous/metachronous colorectal cancers.