Synthesis and evaluation of radioiodinated estrogens for diagnosis and therapy of male urogenital tumours.

The preparation of 24 estrogens, their estrogen receptor (ER) affinity and studies of radioiodinated estrogen binding to ER-positive male bladder tumor cells (HTB9) are described. The estrogens with the highest affinity were selected using fluorescence anisotropy assays. A 2,2,2-trifluoroethyl group at the 11ß-position caused particularly promising affinity. (Radio)iodination was performed on the 17α-vinyl group. Binding studies on HTB9 cells revealed picomolar affinities of radioconjugates 19 and 31, indicating promising ability for targeting of urogenital tumors.

Treatment outcome and identification of factors influencing overall survival after Lu-177-PSMA-617 radioligand therapy in metastatic prostate cancer.

OBJECTIVE: To examine the clinical benefit of Lu-177-PSMA-617 radioligand therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Between November 2014 and December 2018, a total of 56 consecutive patients (median age 69.5 years; range 55-84 years) with mCRPC were included in this retrospective analysis. Patients received between 1 and 4 therapy cycles with a mean activity of 6.8 GBq per cycle. Biochemical response was evaluated using Prostate Cancer Working Group Criteria 3 (PCWG 3). Survival was assessed using Kaplan-Meier estimates and Cox proportional hazards regression analysis. This retrospective study was approved by the local ethics committee. RESULTS: A total of 139 treatment cycles with Lu-177-PSMA-617 were performed. A decline of 50% or more of prostate-specific antigen (PSA) level occurred in 54% and a PSA decline of any amount in 65% of patients. The estimated median overall survival (OS) was 16 months, in the chemotherapy subgroup 14 months. A longer OS was associated with a PSA-decline ≥50%, more than 2 cycles of therapy, cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l]. These identified predictors remained significant on uni- and multivariate Cox regression analysis. Moreover, 40% of the patients who were non-responders after the first therapy cycle turned into responders after the second one. CONCLUSION: PSA-decline ≥50%, a cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l] were identified as key predictors of prolonged OS in patients with mCRPC. In contrast rapid clinical deterioration mostly due to skeletal carcinomatosis resulted in early treatment failure.

Lymph Node Assessment in Prostate Cancer: Evaluation of Iodine Quantification With Spectral Detector CT in Correlation to PSMA PET/CT.

PURPOSE: The aims of this study were to evaluate spectral detector CT (SDCT)-derived iodine concentration (IC) of lymph nodes diagnosed as metastatic and benign in prostate-specific membrane antigen (PSMA) PET/CT and to assess its potential use for lymph node assessment in prostate cancer. PATIENTS AND METHODS: Thirty-four prostate cancer patients were retrospectively included: 16 patients with and 18 without lymph node metastases as determined by PSMA PET/CT. Patients underwent PSMA PET/CT as well as portal venous phase abdominal SDCT for clinical cancer follow-up. Only scan pairs with a stable nodal status indicated by constant size as well as comparable prostate-specific antigen (PSA) levels were included. One hundred benign and 96 suspected metastatic lymph nodes were annotated and correlated between SDCT and PSMA PET/CT. Iodine concentration in SDCT-derived iodine maps and SUVmax in ultra-high definition reconstructions from PSMA PET/CT were acquired based on the region of interest. RESULTS: Metastatic lymph nodes as per PSMA PET/CT showed higher IC than nonmetastatic nodes (1.9 ± 0.6 mg/mL vs 1.5 ± 0.5 mg/mL, P < 0.05) resulting in an AUC of 0.72 and sensitivity/specificity of 81.3%/58.5%. The mean short axis diameter of metastatic lymph nodes was larger than that of nonmetastatic nodes (6.9 ± 3.6 mm vs 5.3 ± 1.3 mm; P < 0.05); a size threshold of 1 cm short axis diameter resulted in a sensitivity/specificity of 12.8%/99.0%. There was a significant yet weak positive correlation between SUVmax and IC (rs = 0.25; P < 0.001). CONCLUSIONS: Spectral detector CT-derived IC was increased in lymph nodes diagnosed as metastatic in PSMA PET/CT yet showed considerable data overlap. The correlation between IC and SUVmax was weak, highlighting the role of PSMA PET/CT as important reference imaging modality for detection of lymph node metastases in prostate cancer patients.

Virtual calcium-suppression in dual energy computed tomography predicts metabolic activity of focal MM lesions as determined by fluorodeoxyglucose positron-emission-tomography.

PURPOSE: Recent studies showed that dual energy CT (DECT) allows for detection of bone marrow infiltration in multiple myeloma (MM) by obtaining virtual non-calcium (VNCa) images. This feasibility study investigated, if VNCa imaging might discriminate metabolically active, focal lesions in MM against avital lesions in MM patients, considering fluorodeoxyglucose positron-emission-tomography CT (FDG PET/CT) as the standard of reference. METHOD: The study included 60 osteolytic lesions in 10 consecutive low-dose whole body CT scans of patients with MM, who underwent both FDG PET/CT and DECT at a tertiary care university hospital. Circular ROI measurements were performed in predefined lesions on the monoenergetic CT (MECT) and VNCa images by three blinded radiologists. Each lesion was rated vital or avital by a blinded specialist of nuclear medicine, based on their FDG metabolism. RESULTS: Each of the three readers could separate FDG PET/CT negative and positive MM lesions when analyzing the VNCa images, while MECT did not show a significant difference. Best results were yielded by high calcium suppression with excellent inter-rater reliability (average sensitivity 0.91, specificity 0.88, cutoff -46.9 HU), followed by medium and low calcium suppression. CONCLUSIONS: In contrast to MECT imaging, VNCa imaging in DECT appears to be feasible to assess metabolic activity of focal MM lesions as defined by the standard of reference, FDG PET/CT. Considering the higher cost and radiation exposure of FDG PET/CT, DECT VNCa imaging might develop to be the modality of choice to assess metabolic activity of focal MM lesions.

An 18F-Labeled PSMA Ligand for PET/CT of Prostate Cancer: First-in-Humans Observational Study and Clinical Experience with 18F-JK-PSMA-7 During the First Year of Application.

In preclinical trials, the recently developed tracer 2-methoxy-18F-DCFPyL (18F-JK-prostate-specific membrane antigen [PSMA]-7) has shown favorable properties regarding clinical performance and radiochemical accessibility. The aim of this study was to evaluate the clinical utility of 18F-JK-PSMA-7 for PET/CT imaging of patients with prostate cancer. Methods: In an Institutional Review Board-approved pilot study, the initial clinical utility of PET/CT imaging with 18F-JK-PSMA-7 was directly compared with 68Ga-PSMA-11 PET/CT in a group of 10 patients with prostate cancer. The 2 PSMA tracers were administered to each patient less than 3 wk apart. Next, we analyzed the data of 75 consecutive patients who had undergone clinical 18F-JK-PSMA-7 PET/CT imaging for tumor localization of biochemical recurrence (BCR). Results: The pilot study in 10 patients who were examined with both PSMA tracers demonstrated that 18F-JK-PSMA-7 was at least equivalent to 68Ga-PSMA-11. All unequivocally 68Ga-PSMA-11-positive lesions could be also detected using 18F-JK-PSMA-7, and in 4 patients additional suspected PSMA-positive lesions were identified (1 patient changed from PSMA-negative to PSMA-positive). In patients with BCR (after prostatectomy or radiotherapy), the capacity of 18F-JK-PSMA-7 PET/CT to detect at least one PSMA-positive lesion was 84.8%. The prostate-specific antigen (PSA)-stratified detection rate of 18F-JK-PSMA-7 after prostatectomy varied among 54.5% (6/11 patients; PSA < 0.5 µg/L), 87.5% (14/16 patients; PSA 0.5-2 µg/L), and 90.9% (20/22 patients; PSA > 2 µg/L). Conclusion: The tracer 18F-JK-PSMA-7 was found to be safe and clinically useful. We demonstrated that 18F-JK-PSMA-7 was not inferior when directly compared with 68Ga-PSMA-11 in a pilot study but indeed identified additional PSMA-avid suspected lesions in oligometastasized patients with BCR. In a subsequent analysis of a clinical cohort of BCR patients, 18F-JK-PSMA-7 was useful in tumor localization. 18F-JK-PSMA-7 is recommended for future prospective trials.

Intraindividual Comparison of 18F-PSMA-1007 with Renally Excreted PSMA Ligands for PSMA PET Imaging in Patients with Relapsed Prostate Cancer.

18F-prostate-specific membrane antigen (PSMA)-1007 is excreted mainly through the liver. We benchmarked the performance of 18F-PSMA-1007 against 3 renally excreted PSMA tracers. Methods: Among 668 patients, we selected 27 in whom PET/CT results obtained with 68Ga-PSMA-11, 18F-DCFPyL (2-(3-(1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid), or 18F-JK-PSMA-7 (JK, Juelich-Koeln) were interpreted as equivocal or negative or as oligometastatic disease (PET-1). Within 3 wk, a second PET scan with 18F-PSMA-1007 was performed (PET-2). The confidence in the interpretation of PSMA-positive locoregional findings was scored on a 5-point scale, first in routine diagnostics (reader 1) and then by an independent second evaluation (reader 2). Discordant PSMA-positive skeletal findings were examined by contrast-enhanced MRI. Results: For both readers, 18F-PSMA-1007 facilitated the interpretability of 27 locoregional lesions. In PET-2, the clinical readout led to a significantly lower number of equivocal locoregional lesions (P = 0.024), and reader 2 reported a significantly higher rate of suspected lesions that were falsely interpreted as probably benign in PET-1 (P = 0.023). Exclusively in PET-2, we observed a total of 15 PSMA-positive spots in the bone marrow of 6 patients (22%). None of the 15 discordant spots had a morphologic correlate on the corresponding CT scan or on the subsequent MRI scan. Thus, 18F-PSMA-1007 exhibits a significantly higher rate of unspecific medullary spots (P = 0.0006). Conclusion:18F-PSMA-1007 may increase confidence in interpreting small locoregional lesions adjacent to the urinary tract but may decrease the interpretability of skeletal lesions.

Biodistribution and radiation dosimetry of [18F]-JK-PSMA-7 as a novel prostate-specific membrane antigen-specific ligand for PET/CT imaging of prostate cancer.

AIM: We investigated the whole-body distribution and the radiation dosimetry of [18F]-JK-PSMA-7, a novel 18F-labeled PSMA-ligand for PET/CT imaging of prostate cancer. METHODS: Ten patients with prostate cancer and biochemical recurrence or radiologic evidence of metastatic diseases were examined with 329-384 MBq (mean 359 ± 17 MBq) [18F]-JK-PSMA-7. Eight sequential positron emission tomography (PET) scans were acquired from 20 min to 3 h after injection with IRB approval. The kidneys, liver, lungs, spleen, and salivary glands were segmented into volumes of interest using the QDOSE dosimetry software suite (ABX-CRO, Germany). Absorbed and effective dose were calculated using the ICRP-endorsed IDAC 1.0 package. The absorbed dose of the salivary glands was determined using the spherical model of OLINDA 1.1. PSMA-positive lesions were evaluated separately. Quantitative assessment of the uptake in suspicious lesions was performed by analysis of maximum (max) and peak SUV values. The gluteus maximus muscle (SUVmean) served as a reference region for the calculation of tumor-to-background ratios (TBR's). RESULTS: Physiologic radiotracer accumulation was observed in the salivary and lacrimal glands, liver, spleen, and intestines, in a pattern resembling the distribution known from other PSMA-tracers with excretion via urinary and biliary pathways. The effective dose from [18F]-JK-PSMA-7 for the whole body was calculated to be 1.09E-02 mGy/MBq. The highest radiation dose was observed in the kidneys (1.76E-01 mGy/MBq), followed by liver (7.61E-02 mGy/MBq), salivary glands (4.68E-02 mGy/MBq), spleen (1.89E-02 mGy/MBq), and lungs (1.10E-2 mGy/MBq). No adverse effects of tracer injection were observed. Six out of ten patients were scored as PSMA-positive. A total of 18 suspicious lesions were analyzed, which included six bone lesions, nine lymph nodes, and three local lesions within the prostate fossa. The values for the SUVmax and SUVpeak in the PSMA-positive lesions increased until 60 min p.i. and remained at this intensity in the PET/CT scans until 140 min. In the period between 170 and 200 min after injection, a further significant increase in SUVmax and SUVpeak within the PSMA-positive lesions was observed. CONCLUSIONS: The highest TBR of [18F]-JK-PSMA-7 was found 3 h after injection. From the kinetically collected data, it can be concluded that this trend may also continue in the further course. The start of the PET/CT acquisition should be chosen as late as possible. The high uptake in suspicious lesions in terms of absolute SUVmax and relative TBR values indicates potentially high sensitivity of the tracer for detection of prostate cancer manifestations.

Uptake in non-affected bone tissue does not differ between [18F]-DCFPyL and [68Ga]-HBED-CC PSMA PET/CT.

INTRODUCTION: [68Ga]PSMA-HBED-CC and [18F]DCFPyL show a high potential for the detection of recurrent prostate cancer. While 18F-based tracers have several advantages in availability and image resolution, their sensitivity in the skeleton might be impaired by released [18F]fluoride due to its high bone affinity. In turn, chemically unbound trivalent 68Ga might also accumulate in osseous tissue, in cases of occupied binding sites of plasma proteins and thereby influence bone signal. METHODS: A comparison of average bone SUV was performed in 17 bone-negative and 4 bone-positive patients. All patients underwent PET/CT 125 minutes after application of [18F]DCFPyL and 73 minutes after application of [68Ga]PSMA-HBED-CC at another date. RESULTS: Native SUVs in unaffected bone tissue and SUVs relative to liver uptake were lower in [18F]DCFPyL (0.49) than in [68Ga]PSMA-HBED-CC scans (0.52). SUVs relative to gluteal muscles did not differ between the two tracers. Average lesional SUVs did not differ between tracers. CONCLUSION: No difference of average bone signal intensity was observed for [18F]DCFPyL-PET/CT in comparison to [68Ga]PSMA-HBED-CC scans indicating that diagnostic assessment of the skeleton is not affected by non-specific accumulation of free [18F]fluoride or 68Ga.

EBONI: A Tool for Automated Quantification of Bone Metastasis Load in PSMA PET/CT.

Prostate-specific membrane antigen (PSMA) PET/CT has a high diagnostic accuracy for lesion detection in metastatic prostate cancer, including bone metastases. Novel therapeutic approaches require valid biomarkers for standardized disease staging and for evaluation of progression and therapy response. Here, we introduce EBONI (Evaluation of Bone Involvement), a software tool to automatically quantify the bone metastasis load in PSMA PET/CT. Lesion quantity, mean and maximum lesional SUV, z score, and percentage of affected bone volume are determined. EBONI is open source and freely available. Methods: To validate EBONI, the results of automated quantification of 38 PSMA PET/CT scans with different levels of bone involvement were compared with visual expert reading. The influence of SUV threshold and Hounsfield unit thresholds was analyzed. Results: A high correlation between bone lesion quantity as determined visually and automatically was found (SUVmax, r2 = 0.97; SUVmean, r2 = 0.88; lesion count, r2 = 0.97). The Hounsfield unit threshold had no significant influence, whereas an SUV threshold of 2.5 proved optimal for automated lesion quantification. The systematic error of false-positive tissue misclassification was low, occurred mainly around the salivary and lacrimal glands, and could easily be corrected. There were no false-negative ratings. Conclusion: EBONI analysis is robust, quick (<3 min per scan), and 100% reproducible. It allows rater-independent quantification of bone metastasis in metastatic prostate cancer. It provides lesion quantification equivalent to that of visual assessment, as well as providing complementary information. It can be easily implemented as an add-on to visual analysis of PSMA PET/CT scans and has the potential to reduce turnaround time.