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[¹⁸F]F-PSMA-1007 Radiolabelling without an On-Site Cyclotron: A Quality Issue.

ABSTRACT: Radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA) has become the gold standard for PET imaging of prostate cancer. [⁶⁸Ga]Ga-PSMA-11 has been the forerunner but a [¹⁸F]F-PSMA ligand has been developed because of the intrinsic advantages of Fluorine-18. Fluorine-18 labelled compounds are usually prepared in centers with an on-site cyclotron. Since our center has not an on-site cyclotron, we decided to verify the feasibility of producing the experimental ¹⁸F^-labelled radiopharmaceutical [¹⁸F]F-PSMA-1007 with [¹⁸F]F^- from different external suppliers. A quality agreement has been signed with two different suppliers, and a well-established and correctly implemented quality assurance protocol has been followed. The [¹⁸F]F^- was produced with cyclotrons, on Nb target, but with different beam energy and current. Extensive validation of the [¹⁸F]F-PSMA-1007 synthesis process has been performed. The aim of this paper was the description of all the quality documentation which allowed the submission and approval of the Investigational Medicinal Product Dossier (IMPD) to the Competent Authority, addressing the quality problems due to different external suppliers. The result indicates that no significant differences have been found between the [¹⁸F]F^- from the two suppliers in terms of radionuclidic and radiochemical purity and [¹⁸F]F^- impacted neither the radiochemical yield of the labelling reaction nor the quality control parameters of the IMP [¹⁸F]F-PSMA-1007. These results prove how a correct quality assurance system can overcome some Regulatory Authorities issue that may represent an obstacle to the clinical use of F-18-labelled radiopharmaceuticals without an on-site cyclotron.

SUBMITTER: Di Iorio V

PROVIDER: S-EPMC8308622 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Due to its high and consistent expression in prostate cancer (PCa), the prostate-specific membrane antigen (PSMA) represents an ideal target for molecular imaging and targeted therapy using highly specific radiolabeled PSMA ligands. To address the continuously growing clinical demand for 18F-labeled PSMA-probes, we developed two novel Glu-urea-Glu-(EuE)-based inhibitors, EuE-k-18F-FBOA (1) and EuE-k-?-a-18F-FPyl (2), both with optimized linker structure and different 18F-labeled aromatic moieties. The inhibitors were evaluated in a comparative preclinical study with 18F-DCFPyl and 18F-PSMA-1007. RESULTS:Radiolabeling procedures allowed preparation of (1) and (2) with high radiochemical yields (67?±?7 and 53?±?7%, d.c.) and purity (>?98%). When compared with 18F-DCFPyl (IC50 = 12.3?±?1.2 nM) and 18F-PSMA-1007 (IC50 = 4.2?±?0.5 nM), both metabolically stable EuE-based ligands showed commensurable or higher PSMA affinity (IC50 = 4.2?±?0.4 nM (1), IC50 = 1.1?±?0.2 nM (2)). Moreover, 1.4- and 2.7-fold higher internalization rates were observed for (1) and (2), respectively, resulting in markedly enhanced tumor accumulation in LNCaP-tumor-bearing mice ((1) 12.7?±?2.0% IA/g, (2) 13.0°?±?1.0% IA/g vs. 7.3?±?1.0% IA/g (18F-DCFPyl), 7.1?±?1.5% IA/g (18F-PSMA-1007), 1 h p.i.). In contrast to (1), (2) showed higher kidney accumulation and delayed clearance kinetics. Due to the high hydrophilicity of both compounds, almost no unspecific uptake in non-target tissue was observed. In contrast, due to the less hydrophilic character (logP?=?-?1.6) and high plasma protein binding (98%), 18F-PSMA-1007 showed uptake in non-target tissue and predominantly hepatobiliary excretion, whereas, 18F-DCFPyl exhibited pharmacokinetics quite similar to those obtained with (1) and (2). CONCLUSION:Both 18F-labeled EuE-based PSMA ligands showed excellent in vitro and in vivo PSMA-targeting characteristics. The substantially higher tumor accumulation in mice compared to recently introduced 18F-PSMA-1007 and 18F-DCFPyl suggests their high value for preclinical studies investigating the effects on PSMA-expression. In contrast to (2), (1) seems to be more promising for further investigation, due to the more reliable 18F-labeling procedure, the faster clearance kinetics with comparable high tumor uptake, resulting therefore in better high-contrast microPET imaging as early as 1 h p.i.

Project description:Simple Summary Since the introduction of PSMA imaging around a decade ago, the faint tracer uptake of ganglia in the neck, abdomen, and presacral region has been an imaging challenge due to difficult discrimination from suspicious lymph nodes. Moreover, PSMA tracers labelled with different radionuclides demonstrate varying levels of ganglion uptake despite having the same target structure on the cell membrane, resulting in distinct imaging pitfall patterns. Our study aims to investigate the underlying mechanisms of the varying detectability of PSMA ligands labelled with different radionuclides. Abstract Background: Several studies indicate, particularly in the case of [18F]PSMA-1007, a relatively high rate of detection of ganglia in PSMA PET imaging. Ganglia are an integral part of the sympathetic portion of the autonomous nervous system. To date, no studies have directly compared [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 ganglionic uptake intra-individually and analyzed the underlying molecular and physical mechanisms of different detection rates. With this monocentric retrospective study, we sought to evaluate the intra-individual physiological ganglion uptake of these different PSMA ligands in evidence-based imaging for prostate cancer. Methods: Our cohort consists of 19 male patients (median age 72 ± 9 with a range of 56–85) with biochemical recurrence of prostate cancer who underwent both [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT in our clinic on the same scanner per standard care between March 2015 and March 2022. Tracer uptake was quantified according to maximum standardized uptake value (SUVmax) for both [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT scans. Ganglia-to-background ratios (GBRs) were determined to quantify the image contrast through dividing the SUVmax of the ganglia by the background value (SUVmax of blood pool in the descending aorta, fatty tissue, and skeletal muscle in gluteal region). We used descriptive analyses for demographics and tumor characteristics and performed two-way repeated-measures ANOVA (analysis of variance) for SUV metrics including GBR measurements. Results: In total, we examined 101 ganglia with [18F]PSMA-1007 scanning, localized mostly in pairs as stellate, coeliac, and sacral, of which 76 were also detected with [68Ga]Ga-PSMA-11 PET/CT scanning. There was no statistically significant difference in PSMA uptake in terms of SUVmax between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 (p value: 0.052). In contrast, the comparison of GBRs revealed a higher detectability rate of ganglia with [18F]PSMA-1007 imaging (p < 0.001). Furthermore, a separate comparison of ganglia with respect to their anatomical location also demonstrated statistically significant differences both within and between [18F]PSMA-1007 and [68Ga]Ga-PSMA-11 PET/CT scans. Conclusion: Given the impression of more accentuated [18F]PSMA-1007 uptake in ganglia compared with 68Ga-labelled counterparts, our study demonstrated that the better detectability of ganglia is not due to more intense [18F]PSMA-1007 uptake by these small structures but to much more favorable physical properties of the radionuclide 18F. The most relevant limitations of our study are its retrospective design and the small patient cohort.

Project description:BackgroundA number of radiopharmaceuticals are available for the detection of recurrent prostate cancer (rPC), but few comparative imaging trials have been performed comparing them. In particular, there are no prospective head-to-head comparisons of the recently introduced [18F]PSMA-1007 to the existing standard of care [68Ga]Ga-PSMA-11. The purpose of this trial is to establish the non-inferiority of the new radiopharmaceutical in terms of the rate of PET-positive findings and to obtain an intra-individual comparison of accuracy and radiopharmaceutical kinetics.MethodsIn this cross-over trial we will randomise 100 individuals to receive either first a standard-of-care PET/CT using [68Ga]Ga-PSMA-11 followed by an additional [18F]PSMA-1007 PET/CT within 2 weeks, or vice-versa. Inclusion criteria include patients 18 years and older with biochemical recurrence of prostate cancer following radical prostatectomy, defined as two consecutive prostate specific antigen (PSA) levels > 0.2 ng/ml. Detection rate at the patient-based level is the primary end-point. Each scan will be interpreted by a panel of six independent and masked readers (three for [68Ga]Ga-PSMA-11 and three for [18F]PSMA-1007) which consensus majority in cases of discrepancy. To confirm the PET-positivity rate at a patient based level, follow up at 6 months following the first scan will be performed to a composite standard of truth. Secondary endpoints shall include an intra-individual comparison of radiopharmaceutical-kinetics, per-region detection rate and positive predictive value.DiscussionThis is the first randomised prospective comparative imaging trial to compare the established [68Ga]Ga-PSMA-11 with [18F]PSMA-1007 and will determine whether the new radiopharmaceutical is non-inferior to the established standard-of-care in terms of patient-level detection rate.Clinical trial registrationRegistered with and approved by the regional ethics authority #2020-02903 (submitted 09.12.2020, approval 16.12.2021) and the regulatory authority SwissMedic 2020DR2103. Registered with ClinicalTrials.gov Identifier NCT05079828 and additionally in a national language in the Swiss National Clinical Trials Portal (SNCTP).

Project description:BackgroundPSMA-based alpha therapy using 225Ac-PSMA-I&T provides treatment for metastatic castration-resistant prostate cancer (mCRPC), even after the failure of 177Lu-PSMA radioligand therapy (RLT). In clinical routine, the total tumor volume (TTV) on PSMA PET impacts therapy outcomes and plays an increasing role in mCRPC patients. Hence, we aimed to assess TTV and its changes during 225Ac-PSMA-I&T RLT.MethodsmCRPC patients undergoing RLT with 225Ac-PSMA-I&T with available 18F-PSMA-1007 PET/CT prior to therapy initiation were included. TTV was assessed in all patients using established cut-off values. Image derived, clinical and biochemistry parameters (PSA, LDH, AP, pain score) were analyzed prior to and after two cycles of 225Ac-PSMA. Changes in TTV and further parameters were directly compared and then correlated with established response criteria, such as RECIST 1.1 or mPERCIST.Results13 mCRPC patients were included. The median overall survival (OS) was 10 months. Prior to 225Ac-PSMA RLT, there was no significant correlation between TTV with other clinical parameters (p > 0.05 each). Between short-term survivors (STS, <10 months OS) and long-term survivors (LTS, ≥10 months OS), TTV and PSA were comparable (p = 0.592 & p = 0.286, respectively), whereas AP was significantly lower in the LTS (p = 0.029). A total of 7/13 patients completed two cycles and underwent a follow-up 18F-PSMA-1007 PET/CT. Among these patients, there was a significant decrease in TTV (median 835 vs. 201 mL, p = 0.028) and PSA (median 687 ng/dL vs. 178 ng/dL, p = 0.018) after two cycles of 225Ac-PSMA RLT. Here, percentage changes of TTV after two cycles showed no direct correlation to all other clinical parameters (p > 0.05 each). In two patients, new PET-avid lesions were detected on 18F-PSMA-1007 PET/CT. However, TTV and PSA were decreasing or stable.ConclusionPET-derived assessment of TTV is an easily applicable imaging biomarker independent of other established parameters prior to 225Ac-PSMA RLT in these preliminary follow-up data. Even after the failure of 177Lu-PSMA, patients with extensive TTV seem to profit from RLT. All but one patient who was eligible for ≥2 cycles of 225Ac-PSMA-RLT demonstrated drastic TTV decreases without direct correlation to other biomarkers, such as serum PSA changes. Changes in TTV might hence improve the response assessment compared to standard classifiers by reflecting the current tumor load independent of the occurrence of new lesions.

Project description:AimDespite increasing use for the detection of biochemically recurrent prostate cancer (rPC), the diagnostic accuracy of positron emission tomography/computed tomography (PET/CT) with [18F]PSMA-1007 remains only partially investigated. The aim of this study was to determine the sensitivity (SE), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) for PC-local recurrence and metastases on a per region basis.Materials and methodsOne hundred seventy-seven consecutive patients undergoing [18F]PSMA-1007 PET/CT for rPC were retrospectively analysed. Six body regions were defined: prostate fossa, pelvic lymph nodes (LN), retroperitoneal LN, supradiaphragmatic LN, bones, and soft tissue. A region was counted positive if at least one PSMA-positive lesion suspicious for PC was observed. Confirmation of a true-positive PSMA-avid lesion was defined as positive by histopathology, fall in serum prostate-specific antigen (PSA) (> 50%) after targeted therapy or confirmatory further CT, MRI, PET/CT, or bone scan imaging. Regions where additional imaging was able to confirm the absence of suspicious PC lesions or regions outside exclusively targeted RT with serum PSA decline (> 50%) were counted as true-negative regions. SE, SP, PPV, and NPV were calculated for all six regions.ResultsThe overall PET-positivity rate was 91%. Conclusive follow-up for affirmation or refutation of a PSMA-positive lesion was available for 81/152 patients on a per region basis. In this subgroup, overall sensitivity, specificity, PPV, and NPV were 95% (CI: 0.90-0.98), 89% (CI: 0.83-0.93), 86% (0.80-0.90), and 96% (CI: 0.92-0.98), respectively. On a per region basis, PPV was 97% (CI: 0.83-0.99) for local recurrence, 93% (CI: 0.78-0.98) for pelvic LN, 87% (CI: 0.62-0.96) for retroperitoneal LN, 82% (CI: 0.52-0.95) for supradiaphragmatic LN, and 79% (0.65-0.89) for bone lesions. The number of solid organ metastases (n = 6) was too small for an accurate statistical analysis.ConclusionThe known high PET-positivity rate of [18F]PSMA-1007 PET/CT in rPC was confirmed, with corresponding high (> 90%) sensitivity and NPV on a per region basis. However, overall PPV was limited (86%), particularly for bone lesions (79%), which are a potential diagnostic weaknesses when using this tracer.

Project description:Prostate-specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68 Ga-PSMA-11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68 Ga-PSMA-11 PET was prospectively performed in patients with treatment-naïve HCC on a digital PET scanner using cyclotron-produced 68 Ga. Uptake was graded qualitatively and semi-quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor-associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10-5 ) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = -0.753; P = 1.58 × 10-6 ). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68 Ga-PSMA-11 standardized uptake value: SUVmax (median [range] 9.2 [4.9-28.4]), SUVmean 4.7 (2.4-12.7), and tumor-to-liver background ratio 2 (1.1-11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68 Ga-PSMA-11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

Project description:PurposeThe prostate-specific membrane antigen (PSMA) targeted positron-emitting-tomography (PET) tracer 68Ga-PSMA-11 shows great promise in the detection of prostate cancer. However, 68Ga has several shortcomings as a radiolabel including short half-life and non-ideal energies, and this has motivated consideration of 18F-labelled analogs. 18F-PSMA-1007 was selected among several 18F-PSMA-ligand candidate compounds because it demonstrated high labelling yields, outstanding tumor uptake and fast, non-urinary background clearance. Here, we describe the properties of 18F-PSMA-1007 in human volunteers and patients.MethodsRadiation dosimetry of 18F-PSMA-1007 was determined in three healthy volunteers who underwent whole-body PET-scans and concomitant blood and urine sampling. Following this, ten patients with high-risk prostate cancer underwent 18F-PSMA-1007 PET/CT (1 h and 3 h p.i.) and normal organ biodistribution and tumor uptakes were examined. Eight patients underwent prostatectomy with extended pelvic lymphadenectomy. Uptake in intra-prostatic lesions and lymph node metastases were correlated with final histopathology, including PSMA immunostaining.ResultsWith an effective dose of approximately 4.4-5.5 mSv per 200-250 MBq examination, 18F-PSMA-1007 behaves similar to other PSMA-PET agents as well as to other 18F-labelled PET-tracers. In comparison to other PSMA-targeting PET-tracers, 18F-PSMA-1007 has reduced urinary clearance enabling excellent assessment of the prostate. Similar to 18F-DCFPyL and with slightly slower clearance kinetics than PSMA-11, favorable tumor-to-background ratios are observed 2-3 h after injection. In eight patients, diagnostic findings were successfully validated by histopathology. 18F-PSMA-1007 PET/CT detected 18 of 19 lymph node metastases in the pelvis, including nodes as small as 1 mm in diameter.Conclusion18F-PSMA-1007 performs at least comparably to 68Ga-PSMA-11, but its longer half-life combined with its superior energy characteristics and non-urinary excretion overcomes some practical limitations of 68Ga-labelled PSMA-targeted tracers.

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[¹⁸F]F-PSMA-1007 Radiolabelling without an On-Site Cyclotron: A Quality Issue.

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[18F]F-PSMA-1007 Radiolabelling without an On-Site Cyclotron: A Quality Issue.

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OmicsDI is part of the ELIXIR infrastructure

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[¹⁸F]F-PSMA-1007 Radiolabelling without an On-Site Cyclotron: A Quality Issue.