National programme for the reliability of ionizing radiation measurements based on inter-laboratory comparisons (ILCs): ILC n°2 'radiopharmaceutical activities'.

A national Inter-Laboratory Comparisons (ILCs) programme was organized in Italy in 2022 by the Italian National Institute of Ionizing Radiation Metrology (INMRI), belonging to ENEA (Italian National Agency for New Technologies, Energy and Sustainable Economic Development), under the auspices of the Ministry of Enterprises and Made in Italy (Mimit ex MiSe). Within this ILCs programme, six inter-laboratory comparisons were organized, including the ILC-2 which focused on activity measurements carried out with radionuclide calibrators commonly used in the nuclear medicine departments of the participants. The focus was on three short-lived radionuclides - 99mTc, 18F, 177Lu - commonly employed in nuclear medicine for both diagnostic and therapeutic purposes. All presented results were compared with the reference values provided by ENEA-INMRI to ensure the traceability of measurements to the national primary activity standards. The observed deviation from the reference values of the measured activity were mainly within ± 10% (100% for 18F, 91.7% for 99mTc, 100% for 177Lu). The En statistical estimator was used to assess the participants' ability to estimate uncertainty in the provided activity values. The obtained values revealed that, in certain instances, the involved laboratories did not achieve the correct results for En (with failure rates of 22.7%, 16.7%, 12.5% for 18F, 99mTc, 177Lu, respectively), despite deviations from the reference values falling within the ± 10%. The aim of ILC-2 was to harmonize the activity measurements in the country within the field of nuclear medicine for the specific radionuclides studied and enhance the measurement capabilities of the participants.

Validation of HPLC and TLC analytical methods to determine radiochemical purity of 99mTc-cAbVCAM1-5, a new experimental radiotracer.

Cardiovascular diseases, including fatal myocardial infarctions from atheromatous plaques, are the primary global mortality cause. Detecting stenotic atheromatous plaques is possible through coronary angiography, but vulnerable plaques with eccentric remodeling are undetectable with current diagnostic methods. Addressing this challenge, our group developed a radiopharmaceutical drug targeting vascular cell adhesion molecule 1 (VCAM-1), radiolabeled with technetium-99m. Given the absence of a monograph in the European Pharmacopoeia, and in order to draft the investigational medicinal product documentation, analytical methods had to be validated by high performance liquid chromatography (HPLC) and thin layer chromatography (TLC) to determine the radiochemical purity (RCP) of 99mTc-cAbVCAM1-5. This study therefore presents the results of the validation of analytical methods obtained in this context. The method validation followed the European Association of Nuclear Medicine (EANM) recommendations adapted from ICH Q2(R1), ensuring conformity with specificity, accuracy, repeatability and intermediate precision, linearity, robustness, quantification limit (LoQ), and range criteria. Regarding the results of specificity, both HPLC and TLC methods demonstrated excellent separation of 99mTc-cAbVCAM1-5 from impurities 99mTcO4-. Accuracy results indicated recovery percentages within the range of 99.52-101.40% for the HPLC and 99.51-101.97% for TLC, ensuring reliable measurements for each concentration of 99mTcO4-. Precision of the methods was validated by assessing repeatability and intermediate precision. Linearity was determined over the usual concentrations range and the correlation coefficient was greater than 0.99 for both methods. The limit of quantification was measured by diluting the 99mTcO4- to obtain a signal-to-noise ratio of around 10:1. Under these conditions, we obtained an LOQ of 2.10 MBq/mL for HPLC and 2Mbq/mL for TLC. In conclusion, the analytical methods developed in this study comply with EANM recommendations. This therefore allows us to correctly assess the radiochemical purity of 99mTc-cAbVCAM1-5, a new radiotracer targeting inflammation in vulnerable plaques.

Commissioning of the first hospital-based PET radiopharmaceutical cyclotron in Greece: personnel dose assessment.

The role of18F-fluoro-deoxy-glucose in positron emission tomography (PET) imaging is well established in diagnosis and management of cancer patients. Installations of on-site self-shielded mini cyclotrons are increasing. The Dose on Demand Biomarker Generator BG-75 was installed at Metaxa Cancer Hospital, Greece, in May 2021 and is the first hospital-based PET radiopharmaceutical cyclotron in the country. Personnel expected external exposure was established during commissioning; internal exposure is not expected. Personnel dose was estimated with two methods: survey meter measurements in various locations combined with the time spent in each location, and direct measurement using electronic personal dosemeters. Gamma and neutron radiation readings outside the cyclotron vault were at background levels. Inside the cyclotron vault, the highest recorded radiation readings by the target were 18µSv h-1for both gammas and neutrons with cyclotron in operational mode; at one meter, the values were 5µSv h-1and 4µSv h-1, respectively. The annual expected whole body dose per cyclotron operator is 0.6 mSv, and the respective extremity dose 16 mSv. The annual expected whole body and extremity dose for the radiochemist is 0.3 mSv and 25 mSv, respectively. The respective annual dose estimates for the medical physicists are < 1 mSv. The expected personnel doses are well below the regulatory limits and local as low as reasonably achievable (ALARA) levels. With experience and a robust ALARA program, personnel exposure could be further reduced.

Increasing Analytical Quality by Designing a Thin-Layer Chromatography Scanner Method for the Determination of the Radiochemical Purity of Radiopharmaceutical Sodium Iodide 131I Oral Solution.

The goal of this study was to apply the principles of analytical quality by design (AQbD) to the analytical method for determining the radiochemical purity (PQR) of the radiopharmaceutical sodium iodide 131I oral solution, utilizing thin-layer chromatography (TLC) with a radio-TLC scanner, which also enables the evaluation of product quality. For AQbD, the analytical target profile (ATP), critical quality attributes (CQA), risk management, and the method operable design region (MODR) were defined through response surface methodology to optimize the method using MINITAB® 19 software. This study encompassed the establishment of a control strategy and the validation of the method, including the assessment of selectivity, linearity, precision, robustness, detection limit, quantification limit, range, and the stability of the sample solution. Under the experimental conditions, the method parameters of the TLC scanner were experimentally demonstrated and optimized with an injection volume of 3 µL, a radioactive concentration of 10 mCi/mL, and a carrier volume of 40 µL. Statistical analysis confirmed the method's selectivity for the 131I iodide band Rf of 0.8, a radiochemical impurity IO3- Rf of 0.6, a linearity from 6.0 to 22.0 mCi/mL, and an intermediate precision with a global relative standard deviation (RSD) of 0.624%. The method also exhibited robustness, with a global RSD of 0.101%, a detection limit of 0.09 mCi/mL, and a quantification limit of 0.53 Ci/mL, meeting the prescribed range and displaying stability over time (at 0, 2, and 20 h) with a global RSD of 0.362%, resulting in consistent outcomes. The development of a method based on AQbD facilitated the creation of a design space and an operational space, with comprehensive knowledge of the method's characteristics and limitations. Additionally, throughout all operations, compliance with the acceptance criteria was verified. The method's validity was confirmed under the established conditions, making it suitable for use in the manufacturing process of sodium iodide 131I and application in nuclear medicine services.

Development and validation of an alternative procedure for quantitative quality control analysis of 99mTc-radiopharmaceuticals using a Geiger Müller counter.

BACKGROUND AND OBJECTIVES: In a hospital radiopharmacy with 2a operational level, including the preparation of radiopharmaceuticals from prepared and approved reagent kits, it is common to have a single activimeter or dose calibrator for labeling and fractionation, and to perform the quality controls of the 99mTc-radiopharmaceuticals. In certain cases, the accumulation of radioactive material or accidental contamination of the work area causes the background to exceed the limits to carry out the radiochemical purity analyses and it is necessary to look for viable alternatives. In this work, a Geiger Müller detector (equipped with a probe for measuring surface contamination) frequently used for radioprotection purposes, was validated as an alternative and its performance was compared against the activimeter for 99mTc-radiopharmaceuticals. MATERIALS AND METHODS: Using [99mTc]pertechnetate, systematic studies of error analyses and detector response to activity concentration, activity and measurement time were carried out in liquid matrices and in paper. The results were compared against an activimeter calibrated for [99mTc]Tc. RESULTS: The developed method was used to determine the radiochemical purity of the compounds [99mTc]Tc-MDP and [99mTc]Tc-MIBI by ascending paper chromatography tests, obtaining comparable values to those measured with an activimeter in the same system (within 1% uncertainty) and using the method of vial partitioning in a dedicated equipment. CONCLUSIONS: This work demonstrates that a Geiger Müller detector with a probe for measuring surface contamination can be adequately used to replace other equipment in the control of radiochemical purity in the hospital radiopharmacy.

A proof of principle study using radiopharmaceuticals to quantify and localize container-content interactions in medical syringes.

The sorption of drugs onto their contents is a known phenomenon that is difficult to analyse precisely. The purpose of this study was to present a non-invasive method for locating and quantifying sorption phenomena using radiopharmaceuticals. Radiopharmaceutical are medicines armed with a radionuclide enabling quantification and imaging using dedicated scanners. The sorption of nine different radiopharmaceuticals on 2- and 3-part syringes was investigated. These syringes were filled with the studied radiopharmaceutical solutions and stored immobile for 3 h. At different times ranging from 0 to 180 min, 10 µL were taken from the syringes and the radioactivity of these samples was determined by a gamma counter. 5 radiopharmaceuticals exhibited no significant sorption at any time point in both 2 and 3-parts syringes, but 4 radiopharmaceuticals exhibited sorption losses varying from 20 to 33% after 3 h contact with 3-part-syringes, but no sorption on 2-part syringes at any time point. [99mTc]Tc-tetrofosmine Single Photon Emission Computed Tomography/Computed Tomography imaging indicated clearly that the interactions were located on the rubber plunger of the 3-part-syringes. The specific nature of radiopharmaceuticals allowed their use as an innovative method to quantify and localize drug sorption phenomena.

Transferability of a two-strip method for the quality control of technetium-99m mercaptoacetyltriglycine ([99mTc]Tc-MAG3).

OBJECTIVES: Technetium-99m mercapto-acetyl-triglycine ([99mTc]Tc-MAG3) is a radiopharmaceutical diagnostic agent used in nuclear medicine intended for the exploration of nephrological and urological disorders. Patient safety and reliability of this imaging procedure especially depend on the radiochemical purity (RCP) of the [99mTc]Tc-MAG3 preparation. Recently, the Summary of Product Characteristics (SPC) of NephroMAG, a kit dedicated to [99mTc]Tc-MAG3 preparation, proposed a two-strip thin layer chromatography (TLC) based quality control (QC) method. Also, Straub et al recently proposed another TLC based QC method. We sought to evaluate the transferability of these QC methods in our hospital radiopharmacy and compared them to our currently employed TLC method and radio-HPLC (high-pressure liquid chromatography) to select the most appropriate in the context of hospital radiopharmacy. METHODS: Ten consecutive [99mTc]Tc-MAG3 preparations were controlled using: HPLC combined with a radiodetector (radio-HPLC), a single strip TLC method (method 1) in current use in our centre, a two-strip TLC method described in the SPC (method SPC) and a two-strip TLC method (method 2) described by Straub et al. Quantitative results for the four tested QC methods were measured and compared in terms of RCP (%), sodium pertechnetate ([99mTc]TcO4 -) (%) and duration of analysis (min). RESULTS: RCP was significantly different between method SPC and radio-HPLC (p<0.001) and method 2 (p<0.001). Also, the percentage of [99mTc]TcO4 - was statistically different between the radio-HPLC and the method SPC (p<0.001), but not with the method 1 and method 2 group (p>0.05). The duration of analysis (min) was significantly different between the four QC procedures (p<0.001) with method 2 and method SPC being the quickest. CONCLUSIONS: Our study showed it is possible to transfer and select a quick and reliable QC method for the preparation of NephroMAG kits in our centre. We therefore advise the widespread use of the method from Straub et al in hospital radiopharmacies.

68 Ga-Prostate-Specific Membrane Antigen PET/CT in Ovarian Tumors : Potential to Differentiate Benign and Malignant Tumors Before Surgery: A Preliminary Report.

PURPOSE OF THE REPORT: Ovarian cancer is usually diagnosed in an advanced stage of disease due to the absence of specific symptoms and a lack of sensitive diagnostic methods. Prostate-specific membrane antigen (PSMA) is expressed on prostate cancer cells but can be found in other tumors such as ovarian cancer.The aim of this pilot study was to evaluate the feasibility of using 68 Ga-PSMA-11 PET/CT in detection of ovarian neoplasm before surgical treatment. PATIENTS AND METHODS: Eight women with mean age of 56.0 ± 16.2 years were included in the study. All patients underwent transvaginal ultrasound followed by CT scan of the chest and abdomen as qualification for surgery. Within a 1-week interval, PET/CT was performed on a Siemens Biograph scanner, 60 minutes after injection of 2 MBq/kg 68 Ga-PSMA-11. RESULTS: In 3 cases (37.5%), the 68 Ga-PSMA-11 PET/CT was positive, whereas histological examination confirmed 2 serous ovarian cancer cases and 1 ovarian borderline tumor. The SUV max in the serous ovarian cancer was 8.7 and 4.1, and in the borderline ovarian tumor, it was 13.8. No correlation was found between antigen CA-125 level and 68 Ga-PSMA expression. Range of tumor SUV max was not correlated with stage of disease. The remaining 62.5% (5/8) were negative in 68 Ga-PSMA-11 PET/CT, and histopathology confirmed benign pelvic tumor. CONCLUSIONS: The initial experience supports the potential to use 68 Ga-PSMA-11 in ovarian cancer to differentiate malignant and benign tumors before surgery.This study was approved by the Ethical Committee of the Medical University of Warsaw (KB/2/A/2018).

Development and Validation of an Analytical HPLC Method to Assess Chemical and Radiochemical Purity of [68Ga]Ga-NODAGA-Exendin-4 Produced by a Fully Automated Method.

Background: Glucagon-like peptide 1 receptor (GLP-1R) is preferentially expressed in pancreatic islets, especially in ß-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 ß-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.

Utility of 18F-FDG-PET for detecting acute lymphoblastic leukemia: a case series of pediatric acute lymphoblastic leukemia without hematological symptoms.

Acute leukemia is typically diagnosed from presenting features related to hematological symptoms, but certain patients present with prominent musculoskeletal pain without signs of hematological abnormality. We reviewed the medical records of 58 children diagnosed with acute lymphoblastic leukemia (ALL) at our hospital to evaluate initial features. Forty six of these patients had hematological symptoms, anemia, or hemorrhage (Group H), while 12 patients had prominent musculoskeletal pain without hematological symptoms (Group P). Diagnosis of leukemia took significantly more time for those 12 patients (Group H, 17.1 days; Group P, 48.5 days). In three of the 12 patients in Group P, localized abnormal imaging findings and unremarkable blood test results led to initial diagnoses of chronic recurrent multifocal osteomyelitis, bone fracture, and septic osteomyelitis. However, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) revealed multiple intense bone foci or systemic bone marrow uptake, leading to the diagnosis of ALL. A review of 18F-FDG-PET results from 23 patients with ALL who underwent a PET scan (Group H, n = 15; Group P, n = 8) showed multiple bone foci or systemic bone marrow uptake in all cases. In conclusion, lack of hematological symptoms in ALL patients can delay diagnosis, and 18F-FDG-PET is useful for diagnosing leukemia in such cases.

A generic gas chromatography method for determination of residual solvents in PET radiopharmaceuticals.

A novel gas chromatography (GC) method for quantitation of volatile organic compounds (VOCs) in 18F- and 11C-radiopharmaceuticals listed in the European Pharmacopoeia (Ph. Eur.) was proposed. Optimized chromatographic parameters were used for separation of ethanol, acetone, acetonitrile, tetrahydrofuran (THF), dibromomethane (DBM), 2-dimethylaminoethanol (deanol), N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) which could be detected in radioactive drug samples. The calculated peak resolutions (RS) were higher than 2.0 at ethanol concentration of up to 11 m/m%. Reproducible results could be obtained using base deactivated fused silica wool as packing material of inlet liner. Validation parameters showed excellent linearity (r2 ≥0.9998) in the range from 10 to at least 120% of concentration limit of solvents. The accuracy was determined as recovery of concentrations which ranged from 99.3% to 103.8%. Additionally, the relative standard deviation (RSD) of each solvent for inter-day and intra-day precision were in the range of 0.5-4.2% and 0.4-4.4%, respectively. The limit of quantitation (LOQ) for ethanol, acetone, acetonitrile, THF, DBM, deanol, DMF and DMSO was 0.48, 0.42, 0.43, 0.46, 4.35, 0.73, 0.68 and 0.50 mg/L, respectively. The developed procedure was successively applied for quantitation of ethanol, acetone, acetonitrile and deanol in radioactive drug samples of [11C]methionine, [11C]choline, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET). The proposed GC method applying flame ionization detection (FID) could be adapted in routine quality control of most frequently used positron emission tomography (PET) radiopharmaceuticals to perform the determination of residual solvents with analysis time of 12 min.

Potential of [11C]UCB-J as a PET tracer for islets of Langerhans.

Biomarkers for the measurement of islets of Langerhans could help elucidate the etiology of diabetes. Synaptic vesicle glycoprotein 2 A (SV2A) is a potential marker reported to be localized in the endocrine pancreas. [11C]UCB-J is a novel positron emission tomography (PET) radiotracer that binds to SV2A and was previously evaluated as a synaptic marker in the central nervous system. Here, we evaluated whether [11C]UCB-J could be utilized as a PET tracer for the islets of Langerhans in the pancreas by targeting SV2A. The mRNA transcription of SV2A was evaluated in human isolated islets of Langerhans and exocrine tissue. In vitro autoradiography was performed on pancreas and brain sections from rats and pigs, and consecutive sections were immunostained for insulin. Sprague-Dawley rats were examined with PET-MRI and ex vivo autoradiography at baseline and with administration of levetiracetam (LEV). Similarly, pigs were examined with dynamic PET-CT over the pancreas and brain after administration of [11C]UCB-J at baseline and after pretreatment with LEV. In vivo radioligand binding was assessed using a one-compartment tissue model. The mRNA expression of SV2A was nearly 7 times higher in endocrine tissue than in exocrine tissue (p < 0.01). In vitro autoradiography displayed focal binding of [11C]UCB-J in the pancreas of rats and pigs, but the binding pattern did not overlap with the insulin-positive areas or with ex vivo autoradiography. In rats, pancreas binding was higher than that in negative control tissues but could not be blocked by LEV. In pigs, the pancreas and brain exhibited accumulation of [11C]UCB-J above the negative control tissue spleen. While brain binding could be blocked by pretreatment with LEV, a similar effect was not observed in the pancreas. Transcription data indicate SV2A to be a valid target for imaging islets of Langerhans, but [11C]UCB-J does not appear to have sufficient sensitivity for this application.

[18F]Atorvastatin Pharmacokinetics and Biodistribution in Healthy Female and Male Rats.

Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that are widely used to prevent cardiovascular diseases. However, a series of pleiotropic mechanisms have been associated with statins, particularly with atorvastatin. Therefore, the assessment of [18F]atorvastatin kinetics with positron emission tomography (PET) may elucidate the mechanism of action of statins and the impact of sexual dimorphism, which is one of the most debated interindividual variations influencing the therapeutic efficacy. [18F]Atorvastatin was synthesized via a previously optimized 18F-deoxyfluorination strategy, used for preclinical PET studies in female and male Wistar rats (n = 7 for both groups), and for subsequent ex vivo biodistribution assessment. PET data were fitted to several pharmacokinetic models, which allowed for estimating relevant kinetic parameters. Both PET imaging and biodistribution studies showed negligible uptake of [18F]atorvastatin in all tissues compared with the primary target organ (liver), excretory pathways (kidneys and small intestine), and stomach. Uptake of [18F]atorvastatin was 38 ± 3% higher in the female liver than in the male liver. The irreversible 2-tissue compartment model showed the best fit to describe [18F]atorvastatin kinetics in the liver. A strong correlation (R2 > 0.93) between quantitative Ki (the radiotracer's unidirectional net rate of influx between compartments) and semi-quantitative liver's SUV (standard uptake value), measured between 40 to 90 min, showed potential to use the latter parameter, which circumvents the need for blood sampling as a surrogate of Ki for monitoring [18F]atorvastatin uptake. Preclinical assays showed faster uptake and clearance for female rats compared to males, seemingly related to a higher efficiency for exchanges between the arterial input and the hepatic tissue. Due to the slow [18F]atorvastatin kinetics, equilibrium between the liver and plasma concentration was not reached during the time frame studied, making it difficult to obtain sufficient and accurate kinetic information to quantitatively characterize the radiotracer pharmacokinetics over time. Nevertheless, the reported results suggest that the SUV can potentially be used as a simplified measure, provided all scans are performed at the same time point. Preclinical PET-studies with [18F]atorvastatin showed faster uptake and clearance in female compared to male rats, apparently related to higher efficiency for exchange between arterial blood and hepatic tissue.

Longitudinal evaluation of a novel BChE PET tracer as an early in vivo biomarker in the brain of a mouse model for Alzheimer disease.

Purpose: The increase in butyrylcholinesterase (BChE) activity in the brain of Alzheimer disease (AD) patients and animal models of AD position this enzyme as a potential biomarker of the disease. However, the information on the ability of BChE to serve as AD biomarker is contradicting, also due to scarce longitudinal studies of BChE activity abundance. Here, we report 11C-labeling, in vivo stability, biodistribution, and longitudinal study on BChE abundance in the brains of control and 5xFAD (AD model) animals, using a potent BChE selective inhibitor, [11C]4, and positron emission tomography (PET) in combination with computerised tomography (CT). We correlate the results with in vivo amyloid beta (Aß) deposition, longitudinally assessed by [18F]florbetaben-PET imaging. Methods: [11C]4 was radiolabelled through 11C-methylation. Metabolism studies were performed on blood and brain samples of female wild type (WT) mice. Biodistribution studies were performed in female WT mice using dynamic PET-CT imaging. Specific binding was demonstrated by ex vivo and in vivo PET imaging blocking studies in female WT and 5xFAD mice at the age of 7 months. Longitudinal PET imaging of BChE was conducted in female 5xFAD mice at 4, 6, 8, 10 and 12 months of age and compared to age-matched control animals. Additionally, Aß plaque distribution was assessed in the same mice using [18F]florbetaben at the ages of 2, 5, 7 and 11 months. The results were validated by ex vivo staining of BChE at 4, 8, and 12 months and Aß at 12 months on brain samples. Results: [11C]4 was produced in sufficient radiochemical yield and molar activity for the use in PET imaging. Metabolism and biodistribution studies confirmed sufficient stability in vivo, the ability of [11C]4 to cross the blood brain barrier (BBB) and rapid washout from the brain. Blocking studies confirmed specificity of the binding. Longitudinal PET studies showed increased levels of BChE in the cerebral cortex, hippocampus, striatum, thalamus, cerebellum and brain stem in aged AD mice compared to WT littermates. [18F]Florbetaben-PET imaging showed similar trend of Aß plaques accumulation in the cerebral cortex and the hippocampus of AD animals as the one observed for BChE at ages 4 to 8 months. Contrarily to the results obtained by ex vivo staining, lower abundance of BChE was observed in vivo at 10 and 12 months than at 8 months of age. Conclusions: The BChE inhibitor [11C]4 crosses the BBB and is quickly washed out of the brain of WT mice. Comparison between AD and WT mice shows accumulation of the radiotracer in the AD-affected areas of the brain over time during the early disease progression. The results correspond well with Aß accumulation, suggesting that BChE is a promising early biomarker for incipient AD.

A survey among German-speaking radiation oncologists on PET-based radiotherapy of prostate cancer.

BACKGROUND: Positron emission tomography-(PET) has evolved as a powerful tool to guide treatment for prostate cancer (PC). The aim of this survey was to evaluate the acceptance and use of PET-especially with prostate-specific membrane antigen (PSMA) targeting tracers-in clinical routine for radiotherapy (RT) and the impact on target volume definition and dose prescription. METHODS: We developed an online survey, which we distributed via e-mail to members of the German Society of Radiation Oncology (DEGRO). The survey included questions on patterns of care of RT for PC with/without PET. For evaluation of doses we used the equivalent dose at fractionation of 2 Gy with α/ß = 1.5 Gy [EQD2(1.5 Gy)]. RESULTS: From 109 participants, 78.9% have the possibility to use PET for RT planning. Most centers use PSMA-targeting tracers (98.8%). In 39.5%, PSMA-PET for biochemical relapse after prior surgery is initiated at PSA ≥ 0.5 ng/mL, while 30.2% will perform PET at ≥ 0.2 ng/mL (≥ 1.0 ng/mL: 16.3%, ≥ 2.0 ng/mL: 2.3%, regardless of PSA: 11.7%). In case of PET-positive local recurrence (LR) and pelvic lymph nodes (LNs), 97.7% and 96.5% of the participants will apply an escalated dose. The median total dose in EQD2(1.5 Gy) was 70.00 Gy (range: 56.89-85.71) for LR and 62.00 Gy (range: 52.61-80.00) for LNs. A total number of ≤ 3 (22.0%) or ≤ 5 (20.2%) distant lesions was most often described as applicable for the definition as oligometastatic PC. CONCLUSION: PSMA-PET is widely used among German radiation oncologists. However, specific implications on treatment planning differ among physicians. Therefore, further trials and guidelines for PET-based RT are warranted.

The development and validation of a high performance liquid chromatography method to determine the radiochemical purity of [177Lu]Lu-HA-DOTA-TATE in pharmaceutical preparations.

Lutetium-177 [177Lu] tetra-azacyclododecanetetra-acetic acid [DOTA]-(Tyr3)-octreotate [TATE] ([177Lu]Lu-DOTA-TATE) is a radiopeptide used for peptide receptor radionuclide therapy in patients with neuroendocrine tumours (NETs). This radiopeptide is made by labelling the ligand octreotate with Lutetium-177 using the linker DOTA. After labelling, and before clinical application quality control of the radiopeptide is needed and the radiochemical purity is assessed. Acceptance limits for radiochemical purity should be within 90-110% of the label claim for radiopharmaceuticals for diagnostic use and within 95-105% of the label claim for radiopharmaceuticals for therapeutic use. Moreover, the amount of unlabelled [177Lu]LuCl3 cannot exceed 2% of the radioactive dose. Since no monograph is available for [177Lu]Lu-DOTA-TATE in the European Pharmacopeia (Ph Eur), this article describes the development and validation of a high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection and radiodetection. A Waters Acquity Arc UHPLC system equipped with a Waters 2998 photodiode array (PDA) detector was used coupled to a Berthold Lb 514 Flowstar detector equipped with a BGO-X gamma measuring cell. A reversed phase Symmetry Shield C18 column (4.6 mm × 250 mm, 5 µm) was used for chromatographic separation. A flow of 1.5 mL/min was maintained during analysis, using 0.1% TFA in water as mobile phase A and 0.1% TFA in ACN as mobile phase B. The retention time was around 1.7 min and 13.5 min for [177Lu]LuCl3 and [177Lu]Lu-HA-DOTA-TATE, respectively. Stock solutions of [177Lu]LuCl3 were made by serial dilution and were injected to test for linearity, accuracy and precision, carry over and signal-to-noise ratio. A [177Lu]Lu-HA-DOTA-TATE sample was prepared and injected to determine the carry over. The results showed that the method is linear over a range of 0.300-130 MBq/mL, which covers the range for clinical samples, provided that the clinical sample is diluted ten times before analysis. The LLOQ can be measured accurately even after dilution, with a signal-to-noise ratio of at least 5. In short, the method is accurate, precise and sensitive and can be implemented as part of the quality control of [177Lu]Lu-HA-DOTA-TATE.

Synthesis and Initial Characterization of a Reversible, Selective 18F-Labeled Radiotracer for Human Butyrylcholinesterase.

PURPOSE: A neuropathological hallmark of Alzheimer's disease (AD) is the presence of amyloid-ß (Aß) plaques in the brain, which are observed in a significant number of cognitively normal, older adults as well. In AD, butyrylcholinesterase (BChE) becomes associated with Aß aggregates, making it a promising target for imaging probes to support diagnosis of AD. In this study, we present the synthesis, radiochemistry, in vitro and preliminary ex and in vivo investigations of a selective, reversible BChE inhibitor as PET-tracer for evaluation as an AD diagnostic. PROCEDURES: Radiolabeling of the inhibitor was achieved by fluorination of a respective tosylated precursor using K[18F]. IC50 values of the fluorinated compound were obtained in a colorimetric assay using recombinant, human (h) BChE. Dissociation constants were determined by measuring hBChE activity in the presence of different concentrations of inhibitor. RESULTS: Radiofluorination of the tosylate precursor gave the desired radiotracer in an average radiochemical yield of 20 ± 3 %. Identity and > 95.5 % radiochemical purity were confirmed by HPLC and TLC autoradiography. The inhibitory potency determined in Ellman's assay gave an IC50 value of 118.3 ± 19.6 nM. Dissociation constants measured in kinetic experiments revealed lower affinity of the inhibitor for binding to the acylated enzyme (K2 = 68.0 nM) in comparison to the free enzyme (K1 = 32.9 nM). CONCLUSIONS: The reversibly acting, selective radiotracer is synthetically easily accessible and retains promising activity and binding potential on hBChE. Radiosynthesis with 18F labeling of tosylates was feasible in a reasonable time frame and good radiochemical yield.

Supplemental minimal-activity PET/CT to validate ambiguous findings with less than 1 mSv: Proof of concept.

Short-term follow-up examinations could verify ambiguous findings in PET/CT diagnostics, but are often avoided due to radiation and financial burdens. We demonstrate the feasibility of a focused, minimal-activity PET protocol as a supplemental examination for uncertain findings after standard PET/CT. After changing conditions, e.g. patient positioning, preparation and bypassing an interval as well as a targeted tracer change, an additional examination with less than 1 mSv of additional radiation exposure was performed. Lowered administered activity of radiopharmaceuticals could be compensated by prolonged acquisition time, which was made possible by the limitation to a single body region. A sufficient visual and quantitative image quality of scans could be achieved. In all cases, the ambiguous finding could be clarified, so further diagnostic procedures or unnecessary interventions were avoided.

Ambient and personnel occupational dose assessment in a Hospital's PET/CT center.

This study used thermoluminescent dosimeters (TLDs) to measure cumulative radiation doses in a PET/CT center. It covered 18 areas and four personnel groups. Because the isolated lead shielding separated the patients from the nurses, wearing protective clothing when injecting radiopharmaceuticals was unnecessary. Fingertip doses of the dispensing and nurse groups were below the occupational limit. Current radiopharmaceutical transportation and injection operations in this PET/CT center provide considerable radiation protection to medical personnel.

Extremity Exposure with 99mTc - Labelled Radiopharmaceuticals in Diagnostic Nuclear Medicine.

BACKGROUND: Extremity exposures may raise the risk of cancer induction among radiographers involved in the preparation and administration of technetium-99m labelled radiopharmaceuticals. OBJECTIVE: To estimate finger doses on radiographers at a South African tertiary hospital. METHODS: Adhesive tape was used to securely fix a calibrated thermoluminescent dosimeter (TLD) on fingertips and bases of ring and index fingers of both hands of five radiographers who prepared and administered technetium-99m labelled radiopharmaceuticals. Rubber gloves were worn to avoid TLD contamination. TLDs doses were read with a Harsaw TLD Reader (Model 3500) after a week. RESULTS: Five radiographers prepared and administered technitium-99m labelled radiopharmaceuticals (activity range; 78.20 GBq - 132.78 GBq during a one-week measurement period). A radiographer handling 132.78 GBq received 4.74±0.52 mSv on both hands; 5.52, 4.55, 5.11 and 4.60 mSv on the fingertip of the index finger of the dominant hand (FIDH), fingertip of the ring finger of the dominant hand (FRDH), fingertip of the index finger of the non-dominant hand (FINDH) and fingertip of the ring finger of the non-dominant hand (FRNDH), respectively. The respective doses received on the finger bases were 4.50 mSv, 4.60, 4.21 and 3.48 mSv. The radiographer handling 78.20 GBq received 0.85±0.18 mSv on both hands, 1.04, 1.17, 0.77 and 1 mSv for the FIDH, FRDH, FINDH and FRNDH, respectively, while respective doses for the bases were 0.8, 0.9, 0.6 and 0.8 mSv. CONCLUSION: The extremity exposures were below the annual limit (500 mSv). However, the use of syringe shields could still reduce the finger doses further.