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Background: Technetium-99 m-labelled macroaggregated human serum albumin ([99mTc]Tc-MAA) is commonly used for lung perfusion scintigraphy. The European Pharmacopoeia (Eu.Ph.) specifies thin-layer chromatography (TLC) as the only method to assess its radiochemical purity (RCP). Similarly, TLC is the sole method reported in the literature to evaluate the RCP of Gallium-68-labelled MAA [68 Ga]Ga-MAA, recently introduced for lung perfusion PET/CT imaging. Since [68 Ga]Ga-MAA is prepared from commercial kits originally designed for the preparation of [99mTc]Tc-MAA, it is essential to optimize and validate the preparation methods for [68 Ga]Ga-MAA. Results: We tested a novel, simplified method for the preparation of [68 Ga]Ga-MAA that does not require organic solvents, prewash or final purification steps to remove radioactive impurities. We assessed the final product using radio-TLC, radio-UV-HPLC, and radio SDS-PAGE. Overall, our quality control (QC) method successfully detected [68 Ga]Ga-MAA along with all potential impurities, including free Ga-68, [68 Ga]Ga-HSA, unlabeled HSA, which may occur during labelling process and HEPES residual, a non-toxic but non-human-approved contaminant, used as buffer solution. We then applied our QC system to [68 Ga]Ga-MAA prepared under different conditions (25°–40°–75°–95 °C), thus defining the optimal temperature for labelling. Scanning Electron Microscopy (SEM) analysis of the products obtained through our novel method confirmed that most [68 Ga]Ga-MAA particles preserved the morphological structure and size distribution of unlabeled MAA, with a particle diameter range of 25–50 μm, assuring diagnostic efficacy. Conclusions: We optimized a novel method to prepare [68 Ga]Ga-MAA through a QC system capable of monitoring all impurities of the final products. [ABSTRACT FROM AUTHOR]

Introduction and aim: Atypical or mixed presentations of neurodegenerative disorders may postpone or confound the final diagnosis. Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) radioligands provide target-specific information and may anticipate the diagnosis by "in vivo" detection of the neuropathological substrate, as Aß deposition, nigrostriatal dopaminergic depletion or tau inclusions. This concise review will discuss the potential of PET and SPECT imaging as a solid guide to better characterize atypical phenotypes of neurodegeneration in the clinical routine, with the potential to drive personalized interventions, improve cohort uniformity for clinical trials, and serve as biomarkers for targeted molecular therapies. Material and methods: Literature search was performed focusing on the role of PET and SPECT imaging in assessing atypical phenotypes of neurodegeneration, using the electronic source of database PubMed/MEDLINE and the web-based search engines Google, Google Scholar. Analysis of the literature. New disease-modifying drugs may increase their effect with early initiation, which is especially important in working persons and younger subjects presenting atypical symptoms. In older individuals, the coexistence of neurodegeneration, age-related changes, cerebrovascular lesions, or depression makes challenging a definitive diagnosis. Quantitative tools able to measure tracer distribution increase the accuracy of molecular neuroimaging creating topographic maps that compare subject's data with healthy controls databases. Concusion: Atypical phenotypes may be associated with quantitative key-pattern allowing a more precise and early diagnosis of the neurodegenerative disorder. Finally, quantitative assessment of the pathological substrates allows us to track the disease process and measure treatment response. [ABSTRACT FROM AUTHOR]

In oligo-metastatic renal cell carcinoma (RCC), neither computed tomography (CT) nor bone scan is sensitive enough to detect small tumor deposits hampering early treatment and potential cure. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein expressed in the neo-vasculature of numerous malignant neoplasms, including RCC, that can be targeted by positron emission tomography (PET) using PSMA-targeting radioligands. Our aim was to investigate whether PSMA-expression patterns of renal cancer in the primary tumor or metastatic lesions on immunohistochemistry (IHC) are associated with PET/CT findings using [68Ga]-PSMA-HBED-CC (PSMA-PET/CT). We then analyzed the predictive and prognostic role of the PSMA-PET/CT signal. In this retrospective single-center study we included patients with renal cancer submitted to PSMA-PET/CT for staging or restaging, with tumor specimens available for PSMA-IHC. Clinical information (age, tumor type, and grade) and IHC results from the primary tumor or metastases were collected. The intensity of PSMA expression at IHC was scored into four categories: 0: none; 1: weak; 2: moderate; 3: strong. PSMA expression was also graded according to the proportion of vessels involved (PSMA%) into four categories: 0: none; 1: 1–25%; 2: 25–50%; 3: >50%. The intensity of PSMA expression and PSMA% were combined in a three-grade score: 0–2 absent or mildly positive, 3–4 moderately positive, and 5–6 strongly positive. PSMA scores were used for correlation with PSMA-PET/CT results. Results: IHC and PET scans were available for the analysis in 26 patients (22 ccRCC, 2 papillary RCC, 1 chromophobe, 1 "not otherwise specified" RCC). PSMA-PET/CT was positive in 17 (65%) and negative in 9 patients (35%). The mean and median SUVmax in the target lesion were 34.1 and 24.9, respectively. Reporter agreement was very high for both distant metastasis location and local recurrence (kappa 1, 100%). PSMA-PET detected more lesions than conventional imaging and revealed unknown metastases in 4 patients. Bone involvement, extension, and lesion number were greater than in the CT scan (median lesion number on PET/CT 3.5). The IHC PSMA score was concordant in primary tumors and metastases. All positive PSMA-PET/CT results (15/22 ccRCC, 1 papillary cancer type II, and 1 chromofobe type) were revealed in tumors with strong or moderate PSMA combined scores (3–4 and 5–6). In ccRCC tissue samples, PSMA expression was strong to moderate in 20/22 cases. The SUVmax values correlated to the intensity of PSMA expression which were assessed using IHC (p = 0.01), especially in the ccRCC subgroup (p = 0.009). Median survival was significantly higher in patients with negative PSMA-PET/CT (48 months) compared to patients with a positive scan (24 months, p= 0.001). SUVmax ≥ 7.4 provides discrimination of patients with a poor prognosis. Results of PSMA-PET/CT changed treatment planning. Conclusions: in renal cancer, positive PSMA-PET/CT is strongly correlated to the intensity of PSMA expression on immunohistochemistry in both ccRCC and chromophobe cancer. PSMA-PET/CT signal predicts a poor prognosis confirming its potential as an aggressiveness biomarker and providing paramount additional information influencing patient management. [ABSTRACT FROM AUTHOR]

Background: Nowadays, in Nuclear Medicine, clinically applied radiopharmaceuticals must meet quality release criteria such as high radiochemical purity and radiochemical yield. Many radiopharmaceuticals do not have marketing authorization and have no dedicated monograph within European Pharmacopeia (Ph. Eur.); therefore, general monographs on quality controls (QCs) have to be applied for clinical application. These criteria require standardization and validation in labeling and preparation, including quality controls measurements, according to well defined standard operation procedures. However, QC measurements are often based on detection techniques that are specific to a certain chromatographic system. Several radiosyntheses of [68Ga]Ga-radiopharmaceuticals are more efficient and robust when they are performed with 2-[4-(2-hydroxyethyl)piperazin-1-yl] ethanesulfonic acid (HEPES) buffer, which is considered as an impurity to be assessed in the QC procedure, prior to clinical use. Thus, Ph. Eur. has introduced a thin-layer chromatography (TLC) method to quantify the HEPES amount that is present in [68Ga]Ga-radiopharmaceuticals. However, this is only qualitative and has proven to be unreliable. Here we develop and validate a new high-performance liquid chromatography (UV-Radio-HPLC) method to quantify the residual amount of HEPES in 68Ga-based radiopharmaceuticals. Method: To validate the proposed UV-Radio-HPLC method, a stepwise approach was used, as defined in the guidance document that was adopted by the European Medicines Agency (CMP/ICH/381/95 2014). The assessed parameters are specificity, linearity, precision (repeatability), accuracy, and limit of quantification. A range of concentrations of HEPES (100, 80, 60, 40, 20, 10, 5, 3 μg/mL) were analyzed. Moreover, to test the validity and pertinence of our new HPLC method, we analyzed samples of [68Ga]Ga-DOTATOC; [68Ga]Ga-PSMA; [68Ga]Ga-DOTATATE; [68Ga]Ga-Pentixafor; and [68Ga]Ga-NODAGA-Exendin-4 from different batches that were prepared for clinical use. Results: In the assessed samples, HEPES could not be detected by the TLC method that was described in Ph. Eur. within 4 min incubation in an iodine-saturated chamber. Our developed HPLC method showed excellent linearity between 3 and 100 μg/mL for HEPES, with a correlation coefficient (R2) for calibration curves that was equal to 0.999, coefficients of variation (CV%) < 2%, and percent deviation value of bias from 100% to 5%, in accordance with acceptance criteria. The intra-day and inter-day precision of our method was statistically confirmed and the limit-of-quantification (LOQ) was 3 μg/mL, confirming the high sensitivity of the method. The amount of HEPES that was detected with our developed HPLC method in the tested [68Ga]Ga-radiopharmaceuticals resulted well below the Ph. Eur. limit, especially for [68Ga]Ga-NODAGA-Exendin-4. Conclusions: The TLC method that is described in Ph. Eur. to assess residual HEPES in [68Ga]-based radiopharmaceuticals may not be sufficiently sensitive and thus unsuitable for QC release. Our new HPLC method was sensitive, quantitative, reproducible, and rapid for QCs, allowing us to exactly determine the residual HEPES amount in [68Ga]Ga-radiopharmaceuticals for safe patient administration. [ABSTRACT FROM AUTHOR]

As compared with conventional modalities, PSMA PET/CT showed superior performance in whole-body staging and restaging of patients with RCC and the assessment of lesions that remained unclear on conventional imaging [[5]]. Both the examinations confirmed the numerous bone lesions (a: MIP; b, f, j, n: fused PET/CT images; c, g, k, o: CT images) and he subsequently began therapy with Sunitinib. [Extracted from the article]

Background: Glucagon-like peptide 1 receptor (GLP-1R) is preferentially expressed in pancreatic islets, especially in β-cells, and highly expressed in human insulinomas and gastrinomas. In recent years several GLP-1R–avid radioligands have been developed to image insulin-secreting tumors or to provide a tentative quantitative in vivo biomarker of pancreatic β-cell mass. Exendin-4, a 39-amino acid peptide with high binding affinity to GLP-1R, has been labeled with Ga-68 for imaging with positron emission tomography (PET). Preparation conditions may influence the quality and in vivo behavior of tracers. Starting from a published synthesis and quality controls (QCs) procedure, we have developed and validated a new rapid and simple UV-Radio-HPLC method to test the chemical and radiochemical purity of [68Ga]Ga-NODAGA-exendin-4, to be used in the clinical routine. Methods: Ga-68 was obtained from a 68Ge/68Ga Generator (GalliaPharma®) and purified using a cationic-exchange cartridge on an automated synthesis module (Scintomics GRP®). NODAGA-exendin-4 contained in the reactor (10 µg) was reconstituted with HEPES and ascorbic acid. The reaction mixture was incubated at 100 °C. The product was purified through HLB cartridge, diluted, and sterilized. To validate the proposed UV-Radio-HPLC method, a stepwise approach was used, as defined in the guidance document released by the International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH), adopted by the European Medicines Agency (CMP/ICH/381/95 2014). The assessed parameters are specificity, linearity, precision (repeatability), accuracy, and limit of quantification. Therefore, a range of concentrations of Ga-NODAGA-exendin-4, NODAGA-exendin-4 (5, 4, 3.125, 1.25, 1, and 0.75 μg/mL) and [68Ga]Ga-NODAGA-exendin-4 were analyzed. To validate the entire production process, three consecutive batches of [68Ga]Ga-NODAGA-exendin-4 were tested. Results: Excellent linearity was found between 5–0.75 μg/mL for both the analytes (NODAGA-exendin-4 and 68Ga-NODAGA-exendin-4), with a correlation coefficient (R2) for calibration curves equal to 0.999, average coefficients of variation (CV%) < 2% (0.45% and 0.39%) and average per cent deviation value of bias from 100%, of 0.06% and 0.04%, respectively. The calibration curve for the determination of [68Ga]Ga-NODAGA-exendin-4 was linear with a R2 of 0.993 and CV% < 2% (1.97%), in accordance to acceptance criteria. The intra-day and inter-day precision of our method was statistically confirmed using 10 μg of peptide. The mean radiochemical yield was 45 ± 2.4% in all the three validation batches of [68Ga]Ga-NODAGA-exendin-4. The radiochemical purity of [68Ga]Ga-NODAGA-exendin-4 was >95% (97.05%, 95.75% and 96.15%) in all the three batches. Conclusions: The developed UV-Radio-HPLC method to assess the radiochemical and chemical purity of [68Ga]Ga-NODAGA-exendin-4 is rapid, accurate and reproducible like its fully automated production. It allows the routine use of this PET tracer as a diagnostic tool for PET imaging of GLP-1R expression in vivo, ensuring patient safety. [ABSTRACT FROM AUTHOR]

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is coming up as a superior imaging tool for prostate cancer (PCa). However, its use in primary staging is still debated. The aim of this study was to assess accuracy of 68Ga-PSMA PET/CT in staging patients with intermediate and high risk PCa candidates to radical prostatectomy managed in the Prostate Cancer Unit of our institution., Methods: We retrospectively evaluated patients with biopsy-proven PCa staged through PSMA PET/CT before undergoing radical prostatectomy (RP) with extended pelvic lymph node dissection (ePLND). PET findings were categorized with respect to primary tumor (T), nodal (N) and distant metastasis (M). We analyzed the correspondence between PSMA PET/CT and final histopathological examination., Results: We evaluated 42 men with high and intermediate risk PCa submitted to RP with ePLND. Mean age was 65.5 years (range, 49-76 years) and median preoperative prostate-specific antigen (PSA) was 13 ng/mL (IQR, 8.1-20 ng/mL). Patients in the high-risk group were 23 (54.7%), and the remainders were in the intermediate risk group. The mean risk of lymph node involvement (LNI) using the Memorial Sloan Kettering Cancer Center (MSKCC)-nomogram was 20%. The most common International Society of Urological Pathology (ISUP) grade was 3 (26.19%) after prostate biopsy. PSMA PET/CT showed focal prostatic uptake in 28 patients [mean value of maximum standardized uptake value (SUVmax) 18.5] and detected pelvic lymph node metastases in 6 cases (14.3%) with a median value of SUVmax 4.5 (IQR, 2-6.9). Histopathological examination detected lymph node metastases in seven patients (16.6%). In the only patient with negative PSMA PET/CT pathology revealed the presence of micrometastasis. After histopathological confirmation, sensitivity, specificity, positive and negative predictive values of pre-operative 68Ga-PSMA PET/CT were 85.7%, 100%, 100% and 97%, respectively., Conclusions: In our series, 68Ga-PSMA PET/CT holds high overall diagnostic value for lymph node staging in patients with intermediate and high risk PCa. Accuracy may depend on lymph node size.

Aim: To assess the role of baseline 18 F-fluorodeoxyglucose ([ 18 F]FDG)-positron emission tomography/computed tomography (PET/CT) in predicting response to immunotherapy after 6 months and overall survival (OS) in patients with lung cancer (LC) or malignant melanoma (MM). Materials and Methods: Data from a multicenter, retrospective study conducted between March and November 2021 were analyzed. Patients >18 years old with a confirmed diagnosis of LC or MM, who underwent a baseline [ 18 F]FDG-PET/CT within 1-2 months before starting immunotherapy and had a follow-up of at least 12 months were included. PET scans were examined visually and semiquantitatively by physicians at peripheral centers. The metabolic tumor burden (number of lesions with [ 18 F]FDG-uptake) and other parameters were recorded. Clinical response was assessed at 3 and 6 months after starting immunotherapy, and OS was calculated as the time elapsing between the PET scan and death or latest follow-up. Results: The study concerned 177 patients with LC and 101 with MM. Baseline PET/CT was positive in primary or local recurrent lesions in 78.5% and 9.9% of cases, in local/distant lymph nodes in 71.8% and 36.6%, in distant metastases in 58.8% and 84%, respectively, in LC and in MM patients. Among patients with LC, [ 18 F]FDG-uptake in primary/recurrent lung lesions was more often associated with no clinical response to immunotherapy after 6 months than in cases without any tracer uptake. After a mean 21 months, 46.5% of patients with LC and 37.1% with MM had died. A significant correlation emerged between the site/number of [ 18 F]FDG foci and death among patients with LC, but not among those with MM. Conclusions: In patients with LC who are candidates for immunotherapy, baseline [ 18 F]FDG-PET/CT can help to predict response to this therapy after 6 months, and to identify those with a poor prognosis based on their metabolic parameters. For patients with MM, there was only a weak correlation between baseline PET/CT parameters, response to therapy, and survival.

Background: Glucagon-like peptide 1 receptor (GLP-1R) is preferentially expressed in β-cells, but it is highly expressed in human insulinomas and gastrinomas. Several GLP-1 receptor- avid radioligands have been developed to image insulin-secreting tumors or to provide a quantitative in vivo biomarker of pancreatic β-cell mass. Exendin-4 is a high affinity ligand of the GLP1- R, which is a candidate for being labeled with a PET isotope and used for imaging purposes., Objective: Here, we report the development and validation results of a semi-manual procedure to label [Lys40,Nle14(Ahx-NODAGA)NH2]exendin-4, with Ga-68., Methods: A 68 Ge/ 68 Ga Generator (GalliaPharma®, Eckert and Ziegler) was eluted with 0.1M HCl on an automated synthesis module (Scintomics GRP®). The peptide contained in the kit vial (Radioisotope Center POLATOM) in different amounts (10-20-30 μg) was reconstituted with 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethansulfonic acid (HEPES) solution and 68 GaCl 3 (400-900 MBq), followed by 10 min incubation at 95°C. The reaction solution was then purified through an Oasis HLB column. The radiopharmaceutical product was tested for quality controls (CQs) in accordance with the European Pharmacopoeia standards., Results: The synthesis of [ 68 Ga]Ga-NODAGA-Exendin-4 provided optimal results with 10 μg of peptide, getting the best radiochemical yield (23.53 ± 2.4%), molar activity (100 GBq/μmol) and radiochemical purity (91.69%)., Conclusion: The study developed an imaging tool [ 68 Ga]Ga-NODAGA-Exendin-4, avoiding pharmacological effects of exendin-4, for the clinical community., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Coronavirus disease 2019 (COVID-19) pathology is associated with neoangiogenesis and interstitial pneumonia. 68 Ga-PSMA-11-PET/CT is able to image in vivo PSMA (Prostate-Specific Membrane Antigen) expression on both prostate cancer (PCa) cells and neovasculature endothelial cells. The aim of the case series was to explore pulmonary PSMA expression not related to cancer in patients with PCa and concomitant COVID-19. In this retrospective, multicenter case series, patients who underwent 68 Ga-PSMA-11-PET/CT for PCa and concomitant proven COVID-19 infection were analyzed. Patients were stratified according to 68 Ga-PSMA-11 intensity of uptake in the lung (SUV max ). Low uptake: < blood pool; mild-to-moderate uptake: > blood pool and < liver; intense uptake: > liver. Potential correlation between pulmonary 68 Ga-PSMA-11 uptake not related to PCa and CT patterns typical for COVID-19 was assessed. Nine patients were included, all of them presenting abnormal 68 Ga-PSMA-11 uptake, at different grades: 2/9 low, 6/9 mild-to-moderate, 1/9 high. Uptake distribution was generally bilateral, peripheral and posterior, positively matching with ground-glass CT alterations in 7/9 (78%) patients, while mismatch was observed in 2/9 (22%). 1/9 patients presented PCa lung metastases at 68 Ga-PSMA-11. 68 Ga-PSMA-11-PET/CT detected increased PSMA uptake within the lung, not related to PCa, matching with CT typical COVID-19 patterns in almost all patients. Further studies are needed to evaluate the role of 68 Ga-PSMA-11 PET in COVID-19 patients and the potential role of PSMA overexpression as a biomarker for neoangiogenesis, in both oncological and infective disorders., Competing Interests: None., (AJNMMI Copyright © 2021.)

Background: Due to its overexpression in a variety of tumor types, the chemokine receptor 4 (CXCR4) represents a highly relevant diagnostic and therapeutic target in nuclear oncology. Recently, [ 68 Ga]Ga-DOTA-Pentixafor has emerged as an excellent imaging agent for positron emission tomography (PET) of CXCR4 expression in vivo. Preparation conditions may influence the quality and in vivo behaviour of this tracer and no standard procedure for the quality controls (QCs) is available., Objective: The developed analytical test method was validated because a specific monograph in the Pharmacopoeia is not available for [68Ga]Ga-DOTA-Pentixafor., Method: A stepwise approach was used based on the quality by design (QbD) concept of the ICH Q2 (R1) and Q8 (Pharmaceutical Development) guidelines in accordance with the regulations and requirements of EANM, SNM, IAEA and WHO., Results: The purity and quality of the radiopharmaceutical obtained according to the proposed method were found to be high enough to safely administrate it to patients. Excellent linearity was found between 0.5 and 4 μg/mL, with a correlation coefficient (r 2 ) for calibration curves being equal to 0.999, the average coefficient of variation (CV%) < 2% and average bias% that did not deviate more than 5% for all concentrations., Conclusion: This study developed a new rapid and simple HPLC method of analysis for the routine QCs of [ 68 Ga]Ga-DOTA-Pentixafor to guarantee the high quality of the finished product before release., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)