IAEA activities on 67Cu, 186Re, 47Sc Theranostic radionuclides and Radiopharmaceuticals

Despite interesting properties, the use of 67Cu, 186Re and 47Sc theranostic radionuclides in preclinical studies and clinical trials is curtailed by their limited availability due to a lack of widely established production methods. An IAEA Coordinated Research Project (CRP) was initiated to identify important technical issues related to the production and quality control of these emerging radionuclides and related radiopharmaceuticals, based on the request from IAEA Member States. The international team worked on targetry, separation, quality control and radiopharmaceutical aspects of the radionuclides obtained from research reactors and cyclotrons leading to preparation of a standard recommendations for all Member States. The CRP was initiated in 2016 with fourteen participants from thirteen Member States from four continents. Extraordinary results on the production, quality control and preclinical evaluation of selected radionuclides were reported in this project that was finalized in 2020. The outcomes, outputs and results of this project achieved by participating Member States are described in this minireview

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Enriched water-H2 18 O purification to be used in routine 18FDG production

18O-water obtained from an 2-deoxy-2-[18F]-fluoro-D-glucose (18FDG, Synthera) synthesis unit is used for purification. The purification process consists of ultraviolet (UV) irradiation followed by a distillation in a preevacuated system. After purification, the loss of enriched water was about only 5 per cent. Organic compounds, radioisotopes, trace metals and gases are eliminated efficiently. Results show that there is no significant difference in the production yield of 2-deoxy-2-[18F]-fluoro-D-glucose ([18F]FDG) whether using purified enriched water by the proposed method of purification or using the new enriched water. This method offers the necessary precaution from contamination by tritium during the purification process. The obtained 18FDG or Na-18F using the purified 18O-water is of tritium free

Synthesis and in vivo evaluation of both (2R,3R)-[123I]- and (2S,3S)- -[123I]-trans-2-hydroxy-5-((E)-3-(iodo) allyloxy)-3-(4-phenyl-1-piperazinyl) tetralin as SPECT radiotracer

We report the synthesis of enantiopure benzovesamicol derivatives: (2R,3R)-[123I]-trans-2-hydroxy-5-((E)-3- -(iodo)allyloxy)-3-(4-phenyl-1-piperazinyl) tetralin and (2S,3S)-[123I]-trans-2-hydroxy-5-((E)-3-(iodo)allyloxy)-3-(4- phenyl-1-piperazinyl) tetralin; [(2R,3R)-[123I]-1 and (2S,3S)-[123I]-1]. Both compounds were obtained with radiochemical and optical purities greater than 97% and with radiochemical yields in the range of 50–60%. To determine whether these compounds could have potential advantage compared to [125I]-iodo benzovesamicol (IBVM), IBVM was also labelled and used as the reference compound in all in vivo experiments. Both (2R,3R)-[123I]-1 and (-)-[125I]-IBVM showed similar time activity curves (TACs) with the highest accumulations in the striatum region followed by the cortex, hippocampus and then cerebellum. While (2S,3S)-[123I]-1 showed an overall homogeneous brain distribution. However, time activity curves of (2R,3R)-[123I]-1 confirmed that this compound could be used to visualize the vesicular acetylcholine transporter (VAChT) in vivo, at each point of the kinetic study. Also (2R,3R)-[123I]-1 showed lower specific bindings compared to [125I]-IBVM. These results suggested that (2R,3R)-[123I]-1 is inferior in comparison with [125I]-IBVM for in vivo VAChT exploration

Routine simultaneous production of no-carrier-added high purity 64Cu and 67Ga

A routine production method of no-carrier-added 64Cu was performed. A copper target support is electroplated by gold then an optimized thickness of enriched 68Zn layer is deposited. The 68Zn target was bombarded with a 23.5 MeV and 250 miA proton beam, generating the main nuclear reactions 68Zn(p,2n)67Ga and 68Zn(p,alfa n)64Cu. A semi-automated separation method using a chromatographic column system was developed for 64CuCl2 production. A 600 mCi batch of 64Cu is produced at the end of separation and purification chemistry. The radionuclidic purity of 64Cu was less than 98% as required by the United States and European Pharmacopoeias. Radiochemical purity and activity concentration is suitable for labeling different ligands to produce diagnostic and therapeutic radiopharmaceuticals

Synthesis and biodistribution of both (±)-5-[ 18F]-fluoroethoxy and (±)-5-[ 18F]-fluoropropoxy piperazine analogs of benzovesamicol as vesicular acetylcholine transporter ligands (VAChT)

The radiosynthesis and preliminary biological evaluation in rats’ brain of two novel piperazine analogs of benzovesamicol as ligands for the vesicular acetylcholine transporter (VAChT) have been carried out. The novel benzovesamicol derivatives 5-(2-fluoroethoxy)-3-(4-phenylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-ol and 5-(3-fluoropropoxy)-3-(4-phenylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-ol [(±)-[18F]-6 and (±)-[18F]-7] were successfully labelled with fluorine-18 from their tosylate precursors, with radiochemical purities greater than 98% and with radiochemical yield in the range of 5–6%. To determine whether these compounds could have potential advantage compared to [125I]-iodo benzovesamicol (IBVM), IBVM was also labelled and used as the reference compound in all in vivo experiments. Both (±)-[18F]-6 and (±)-[18F]-7 showed lower specific binding in all brain areas explored 2 h post injection when compared to reference compound (-)-[125I] IBVM. Furthermore, defluorination indicated that (±)-[18F]-6 and (±)-[18F]-7 are not suitable as radioligands to explore the VAChT in vivo by PET. Moreover, it is well known that interaction at the VAChT binding site is enantioselective, and therefore, working with enantiomerically pure compounds, could improve the compound activity

Radiosynthesis and biological evaluation of 123I-(±)-trans-2-hydroxy-5-((E)- -3-(iodo)allyloxy)-3-(4-phenyl-1-piperazinyl) tetralin

This work reports both the radiolabeling and preliminary biodistribution results in the rat brains of (±)-[123I]- -II. The novel benzovesamicol derivative (±)-[123I]-II was successfully labeled with iodine-123 from its corresponding n-tributyltin, with radiochemical purity greater than 97% and radiochemical yield in the range 50–55%. (±)-[123I]-II showed a higher accumulation in striatum than in the other regions studied. To determine if (±)-[123I]-II could provide an advantage compared to reference compound [125I]-IBVM a kinetic study was carried out, at each point of the kinetic study, (±)-[123I]-II showed a lower specific binding compared to [125I]-IBVM. Time activity curves of (±)-[123I]-II confirmed that this compound is inferior to [125I]-IBVM to explore the VAChT in vivo by SPECT. Moreover, it is well known that interaction at the VAChT binding site is enantioselective, and therefore, working with enantiomerically pure compounds, could improve the compound activity