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18 F-labeled somatostatin analogs (SSAs) could represent a valid alternative to the current gold standard, 68 Ga-labeled SSAs, for somatostatin receptor imaging in patients with neuroendocrine tumors (NETs), given their logistic advantages. Recently, 18 F-AlF-NOTA-octreotide ( 18 F-AlF-OC) has emerged as a promising candidate, but a thorough comparison with 68 Ga-DOTA-SSA in large patient groups is needed. This prospective, multicenter trial aims to demonstrate noninferiority of 18 F-AlF-OC compared with 68 Ga-DOTA-SSA PET in NET patients (ClinicalTrials.gov, NCT04552847). Methods: Seventy-five patients with histologically confirmed NET and routine clinical 68 Ga-DOTATATE ( n = 56) or 68 Ga-DOTANOC ( n = 19) PET, performed within a 3-mo interval of the study scan (median, 7 d; range, -30 to +32 d), were included. Patients underwent a whole-body PET 2 h after intravenous injection of 4 MBq/kg of 18 F-AlF-OC. A randomized, masked consensus read was performed by 2 experienced readers to count tumor lesions. After unmasking, the detection ratio (DR) was determined for each scan, that is, the fraction of lesions detected on a scan compared with the union of lesions of both scans. The differential DR (DDR; difference in DR between 18 F-AlF-OC and 68 Ga-DOTATATE/NOC) per patient was calculated. Tracer uptake was evaluated by comparing SUV max and tumor-to-background ratios in concordant lesions. Results: In total, 4,709 different tumor lesions were detected: 3,454 with 68 Ga-DOTATATE/NOC and 4,278 with 18 F-AlF-OC. The mean DR with 18 F-AlF-OC was significantly higher than with 68 Ga-DOTATATE/NOC (91.1% vs. 75.3%; P < 10 -5 ). The resulting mean DDR was 15.8%, with a lower margin of the 95% CI (95% CI, 9.6%-22.0%) higher than -15%, which is the prespecified boundary for noninferiority. The mean DDRs for the 68 Ga-DOTATATE and 68 Ga-DOTANOC subgroups were 11.8% (95% CI, 4.3-19.3) and 27.5% (95% CI, 17.8-37.1), respectively. The mean DDR for most organs was higher than zero, except for bone lesions (mean DDR, -2.8%; 95% CI, -17.8 to 12.2). No significant differences in mean SUV max were observed ( P = 0.067), but mean tumor-to-background ratio was significantly higher with 18 F-AlF-OC than with 68 Ga-DOTATATE/NOC (31.7 ± 36.5 vs. 25.1 ± 32.7; P = 0.001). Conclusion: 18 F-AlF-OC is noninferior and even superior to 68 Ga-DOTATATE/NOC PET in NET patients. This validates 18 F-AlF-OC as an option for clinical practice somatostatin receptor PET., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: The widespread use of gallium-68-labelled somatostatin analogue (SSA) PET, the current standard for somatostatin receptor (SSTR) imaging, is limited by practical and economic challenges that could be overcome by a fluorine-18-labelled alternative, such as the recently introduced [ 18 F]AlF-NOTA-octreotide ([ 18 F]AlF-OC). This prospective trial aimed to evaluate safety, dosimetry, biodistribution, pharmacokinetics and lesion targeting of [ 18 F]AlF-OC and perform the first comparison with [ 68 Ga]Ga-DOTATATE in neuroendocrine tumour (NET) patients., Methods: Six healthy volunteers and six NET patients with a previous clinical [ 68 Ga]Ga-DOTATATE PET were injected with an IV bolus of 4 MBq/kg [ 18 F]AlF-OC. Healthy volunteers underwent serial whole-body PET scans from time of tracer injection up to 90 min post-injection, with an additional PET/CT at 150 and 300 min post-injection. In patients, a 45-min dynamic PET was acquired and three whole-body PET scans at 60, 90 and 180 min post-injection. Absorbed organ doses and effective doses were calculated using OLINDA/EXM. Normal organ uptake (SUV mean ) and tumour lesion uptake (SUV max and tumour-to-background ratio (TBR)) were measured. A lesion-by-lesion analysis was performed and the detection ratio (DR), defined as the fraction of detected lesions was determined for each tracer., Results: [ 18 F]AlF-OC administration was safe and well tolerated. The highest dose was received by the spleen (0.159 ± 0.062 mGy/MBq), followed by the urinary bladder wall (0.135 ± 0.046 mGy/mBq) and the kidneys (0.070 ± 0.018 mGy/MBq), in accordance with the expected SSTR-specific uptake in the spleen and renal excretion of the tracer. The effective dose was 22.4 ± 4.4 μSv/MBq. The physiologic uptake pattern of [ 18 F]AlF-OC was comparable to [ 68 Ga]Ga-DOTATATE. Mean tumour SUV max was lower for [ 18 F]AlF-OC (12.3 ± 6.5 at 2 h post-injection vs. 18.3 ± 9.5; p = 0.03). However, no significant differences were found in TBR (9.8 ± 6.7 at 2 h post-injection vs. 13.6 ± 11.8; p = 0.35). DR was high and comparable for both tracers (86.0% for [ 68 Ga]Ga-DOTATATE vs. 90.1% for [ 18 F]AlF-OC at 2 h post-injection; p = 0.68)., Conclusion: [ 18 F]AlF-OC shows favourable kinetic and imaging characteristics in patients that warrant further head-to-head comparison to validate [ 18 F]AlF-OC as a fluorine-18-labelled alternative for gallium-68-labelled SSA clinical PET., Trial Registration: Clinicaltrials.gov : NCT03883776, EudraCT: 2018-002827-40.

Background: Gallium-68 labeled synthetic somatostatin analogs for PET/CT imaging are the current gold standard for somatostatin receptor imaging in neuroendocrine tumor patients. Despite good imaging properties, their use in clinical practice is hampered by the low production levels of 68 Ga eluted from a 68 Ge/ 68 Ga generator. In contrast, 18 F-tracers can be produced in large quantities allowing centralized production and distribution to distant PET centers. [ 18 F]AlF-NOTA-octreotide is a promising tracer that combines a straightforward Al 18 F-based production procedure with excellent in vivo pharmacokinetics and specific tumor uptake, demonstrated in SSTR2 positive tumor mice. However, advancing towards clinical studies with [ 18 F]AlF-NOTA-octreotide requires the development of an efficient automated GMP production process and additional preclinical studies are necessary to further evaluate the in vivo properties of [ 18 F]AlF-NOTA-octreotide. In this study, we present the automated GMP production of [ 18 F]AlF-NOTA-octreotide on the Trasis AllinOne® radio-synthesizer platform and quality control of the drug product in accordance with GMP. Further, radiometabolite studies were performed and the pharmacokinetics and biodistribution of [ 18 F]AlF-NOTA-octreotide were assessed in healthy rats using μPET/MR., Results: The production process of [ 18 F]AlF-NOTA-octreotide has been validated by three validation production runs and the tracer was obtained with a final batch activity of 10.8 ± 1.3 GBq at end of synthesis with a radiochemical yield of 26.1 ± 3.6% (dc), high radiochemical purity and stability (96.3 ± 0.2% up to 6 h post synthesis) and an apparent molar activity of 160.5 ± 75.3 GBq/μmol. The total synthesis time was 40 ± 3 min. Further, the quality control was successfully implemented using validated analytical procedures. Finally, [ 18 F]AlF-NOTA-octreotide showed high in vivo stability and favorable pharmacokinetics with high and specific accumulation in SSTR2-expressing organs in rats., Conclusion: This robust and automated production process provides high batch activity of [ 18 F]AlF-NOTA-octreotide allowing centralized production and shipment of the compound to remote PET centers. Further, the production process and quality control developed for [ 18 F]AlF-NOTA-octreotide is easily implementable in a clinical setting and the tracer is a potential clinical alternative for somatostatin directed 68 Ga labeled peptides obviating the need for a 68 Ge/ 68 Ga-generator. Finally, the favorable in vivo properties of [ 18 F]AlF-NOTA-octreotide in rats, with high and specific accumulation in SSTR2 expressing organs, supports clinical translation.

Positron emission tomography (PET) is a quickly expanding, non-invasive molecular imaging technology, and there is high demand for new specific imaging probes. Herein, we present a generic protocol for direct radiolabeling of heat-sensitive biomolecules with the positron-emitting radioisotope fluorine-18 ( 18 F) using the aluminum fluoride restrained complexing agent (Al 18 F-RESCA) method. The Al 18 F-RESCA method combines the chemical advantages of a chelator-based radiolabeling method with the unique physical properties of the radionuclide of choice, fluorine-18. Proteins of interest can be conjugated to RESCA via amine coupling using (±)-H 3 RESCA-TFP, followed by purification using size-exclusion chromatography (SEC). Next, RESCA-derivatized biomolecules can be labeled in one step, at room temperature (~20 °C) in an aqueous medium with aluminum fluoride (Al 18 F). Al 18 F-labeled proteins can be obtained with moderate (12-17 GBq/µmol) to good (80-85 GBq/µmol) apparent molar activity, depending on the starting activity of 18 F - . In addition, satisfactory radiochemical yields (35-55%, non-decay corrected) and high radiochemical purity (>98%, using gel filtration or solid-phase purification) are obtained. The mild radiolabeling procedure takes 0.5 h to complete and can be used for direct labeling of vector molecules such as peptides, protein scaffolds, and engineered antibody fragments.

Introduction: Grief is a universal experience faced at one time or another by most people during their lives. Response to grief and bereavement losses can lead to psychiatric disorders such as mood disorders, post traumatic responses, insomnia loss of appetite, anxiety, and depression. The aim of our study is to value in our community the physical and psychological complications of a normal grief., Methods: We conducted a cross-sectional study from March 2012 to September 2012 in Lubumbashi, Democratic Republic of Congo. Two questionnaires, the Hamilton Anxiety Scale and the Beck Depression Inventory scale were used as screening tool. A snow ball sampling method was performed and the questionnaires were administered only to those who consented to participate in the study., Results: A total of 78 subjects were included in the study of which 87.2% were aged between 14-50 years old. The majority of the subjects were female 65.4%, and about a quarter (28%) was unemployed. The main correlates of the grief reported in the present study were being treated as witchcraft or accused to be responsible of a death (68%), being rejected by family and not being allowed to inherit (32%). Being homeless was reported in 26%. The main psychological symptoms reported were psychological distress after 1 year (65%) and related physical health problems after the death (72%). Depression and mild anxiety were the most reported disorders, with respectively 92.3% and 74.4% of the subjects., Conclusion: Grief in Lubumbashi is associated with a large number of psychological, social and health problems. Health problems such as gastric is, high blood pressure were often reported. Being accused of witchcraft remains the main social impact. Depression and anxiety were the most psychological problem associated with grief.

Recombinant adeno-associated virus (rAAV) vectors mediating long term transgene expression are excellent gene therapy tools for chronic neurological diseases. While rAAV2 was the first serotype tested in the clinics, more efficient vectors derived from the rh10 serotype are currently being evaluated and other serotypes are likely to be tested in the near future. In addition, aside from the currently used stereotaxy-guided intraparenchymal delivery, new techniques for global brain transduction (by intravenous or intra-cerebrospinal injections) are very promising. Various strategies for therapeutic gene delivery to the central nervous system have been explored in human clinical trials in the past decade. Canavan disease, a genetic disease caused by an enzymatic deficiency, was the first to be approved. Three gene transfer paradigms for Parkinson's disease have been explored: converting L-dopa into dopamine through AADC gene delivery in the putamen; synthesizing GABA through GAD gene delivery in the overactive subthalamic nucleus and providing neurotrophic support through neurturin gene delivery in the nigro-striatal pathway. These pioneer clinical trials demonstrated the safety and tolerability of rAAV delivery in the human brain at moderate doses. Therapeutic effects however, were modest, emphasizing the need for higher doses of the therapeutic transgene product which could be achieved using more efficient vectors or expression cassettes. This will require re-addressing pharmacological aspects, with attention to which cases require either localized and cell-type specific expression or efficient brain-wide transgene expression, and when it is necessary to modulate or terminate the administration of transgene product. The ongoing development of targeted and regulated rAAV vectors is described., (© 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.)