Simplified and Highly-Reliable Automated Production of [8F]FSPG for Clinical Studies

Background: (S)-4-(3-18F-Fluoropropyl)-L-Glutamic Acid ([18F]FSPG) is a positron emission tomography (PET) tracer that specifically targets the cystine/glutamate antiporter (xc-), which is frequently overexpressed in cancer and several neurological disorders. Pilot studies examining the dosimetry and biodistribution of [18F]FSPG in healthy volunteers and tumor detection in patients with non-small cell lung cancer, hepatocellular carcinoma, and brain tumors showed promising results. In particular, low background uptake in the brain, lung, liver, and bowel was observed that further leads to excellent imaging contrasts of [18F]FSPG PET. However, reliable production-scale cGMP-compliant automated procedures for [18F]FSPG production are still lacking to further increase the utility and clinical adoption of this radiotracer. Herein, we report the optimized automated approaches to produce [18F]FSPG through two commercially available radiosynthesizers capable of supporting centralized and large-scale production for clinical use. Results: Starting with activity levels of 60-85 GBq, the fully-automated process to produce [18F]FSPG took less than 45 min with average radiochemical yields of 22.56 ± 0.97% and 30.82 ± 1.60% (non-decay corrected) using TRACERlab™ FXFN and FASTlab™, respectively. The radiochemical purities were \u3e 95% and the formulated [18F]FSPG solution was determined to be sterile and colorless with the pH of 6.5-7.5. No radiolysis of the product was observed up to 8 h after final batch formulation. Conclusions: In summary, cGMP-compliant radiosyntheses and quality control of [18F]FSPG have been established on two commercially available synthesizers leveraging high activity concentration and radiochemical purity. While the clinical trials using [18F]FSPG PET are currently underway, the automated approaches reported herein will accelerate the clinical adoption of this radiotracer and warrant centralized and large-scale production of [18F]FSPG

One-loop contributions to decays eb→eaγe_b\to e_a \gamma and (g−2)ea(g-2)_{e_a} anomalies, and Ward identity

In this paper, we will present analytic formulas to express one-loop contributions to lepton flavor violating decays $e_b\to e_a \gamma$, which are also relevant to the anomalous dipole magnetic moments of charged leptons $e_a$. These formulas were computed in the unitary gauge, using the well-known Passarino-Veltman notations. We also show that our results are consistent with those calculated previously in the 't Hooft-Veltman gauge, or in the limit of zero lepton masses. At the one-loop level, we show that the appearance of fermion-scalar-vector type diagrams in the unitary gauge will violate the Ward Identity relating to an external photon. As a result, the validation of the Ward Identity guarantees that the photon always couples with two identical particles in an arbitrary triple coupling vertex containing a photon.Comment: The version accepted to Nuclear Physics

cGMP Compliant One-Step, One-Pot Automated [18F]FBnTP Production for Clinical Imaging of Mitochondrial Activity

Background 4-[18F]fluorobenzyl-triphenylphosphonium ([18F]FBnTP) is a lipophilic cation PET tracer. The cellular uptake of [18F]FBnTP is correlated with oxidative phosphorylation by mitochondria, which has been associated with multiple critical diseases. To date, [18F]FBnTP has been successfully applied for imaging myocardial perfusion, assessment of severity of coronary artery stenosis, delineation of the ischemic area after transient coronary occlusion, and detection/quantification of apoptosis in various animal models. Recent preclinical and clinical studies have also expanded the possibilities of using [18F]FBnTP in oncological diagnosis and therapeutic monitoring. However, [18F]FBnTP is typically prepared through a tediously lengthy four-step, three-pot reaction and required multiple synthesizer modules; Thus, such an approach remains a challenge for this promising radiopharmaceutical to be implemented for routine clinical studies. Herein, we report an optimized one-step, one-pot automated approach to produce [18F]FBnTP through a single standard commercially-available radiosynthesizer that enables centralized production for clinical use. Results The fully automated production of [18F]FBnTP took less than 55 min with radiochemical yields ranging from 28.33 ± 13.92% (non-decay corrected), apparent molar activity of 69.23 ± 45.62 GBq/µmol, and radiochemical purities of 99.79 ± 0.41%. The formulated [18F]FBnTP solution was determined to be sterile and colorless with a pH of 4.0–6.0. Our data has indicated no observable radiolysis after 8 h from the time of final product formulation and maximum assay of 7.88 GBq. Conclusions A simplified and cGMP-compliant radiosynthesis of [18F]FBnTP has been established on the commercially available synthesizer in high activity concentration and radiochemical purity. While the preclinical and clinical studies using [18F]FBnTP PET are currently underway, the automated approaches reported herein facilitate clinical adoption of this radiotracer and warrant centralized production of [18F]FBnTP for imaging multiple patients

Stochastic modelling of the correlation between transformer loading and distributed energy resources in LV distribution networks

The rapid growth of distributed energy resources (DERs) poses operational challenges for the low-voltage (LV) distribution networks, such as overloading of the transformer and/or voltage violation. Many smart strategies based on flexibility and coordinated control of DER have been developed to address these issues. To facilitate this implementation, this study presents a stochastic modelling technique, based on the Monte Carlo approach, to analyse the correlation between transformer loading and voltage magnitudes measured at the point of connection (POC) of DER in the network. A case study has been performed using IEEE European LV test feeder and smart meter measurement from the Netherlands to reflect the realistic aspects of operational conditions. Advanced statistical modelling techniques are applied to generate a set of scenarios, consisting of solar irradiation, and electric vehicle charging and load consumption profiles. Simulation results reveal a strong linear relationship between transformer loading and voltage magnitudes at the POC of DERs. Thus, these findings can aid in implementing flexibility and coordinated control DERs for congestion management in the LV distribution network.</p

Stochastic modelling of the correlation between transformer loading and distributed energy resources in LV distribution networks

The rapid growth of distributed energy resources (DERs) poses operational challenges for the low-voltage (LV) distribution networks, such as overloading of the transformer and/or voltage violation. Many smart strategies based on flexibility and coordinated control of DER have been developed to address these issues. To facilitate this implementation, this study presents a stochastic modelling technique, based on the Monte Carlo approach, to analyse the correlation between transformer loading and voltage magnitudes measured at the point of connection (POC) of DER in the network. A case study has been performed using IEEE European LV test feeder and smart meter measurement from the Netherlands to reflect the realistic aspects of operational conditions. Advanced statistical modelling techniques are applied to generate a set of scenarios, consisting of solar irradiation, and electric vehicle charging and load consumption profiles. Simulation results reveal a strong linear relationship between transformer loading and voltage magnitudes at the POC of DERs. Thus, these findings can aid in implementing flexibility and coordinated control DERs for congestion management in the LV distribution network.</p

Loss of α-Synuclein Does Not Affect Mitochondrial Bioenergetics in Rodent Neurons.

Increased α-synuclein (αsyn) and mitochondrial dysfunction play central roles in the pathogenesis of Parkinson's disease (PD), and lowering αsyn is under intensive investigation as a therapeutic strategy for PD. Increased αsyn levels disrupt mitochondria and impair respiration, while reduced αsyn protects against mitochondrial toxins, suggesting that interactions between αsyn and mitochondria influences the pathologic and physiologic functions of αsyn. However, we do not know if αsyn affects normal mitochondrial function or if lowering αsyn levels impacts bioenergetic function, especially at the nerve terminal where αsyn is enriched. To determine if αsyn is required for normal mitochondrial function in neurons, we comprehensively evaluated how lowering αsyn affects mitochondrial function. We found that αsyn knockout (KO) does not affect the respiration of cultured hippocampal neurons or cortical and dopaminergic synaptosomes, and that neither loss of αsyn nor all three (α, β and γ) syn isoforms decreased mitochondria-derived ATP levels at the synapse. Similarly, neither αsyn KO nor knockdown altered the capacity of synaptic mitochondria to meet the energy requirements of synaptic vesicle cycling or influenced the localization of mitochondria to dopamine (DA) synapses in vivo. Finally, αsyn KO did not affect overall energy metabolism in mice assessed with a Comprehensive Lab Animal Monitoring System. These studies suggest either that αsyn has little or no significant physiological effect on mitochondrial bioenergetic function, or that any such functions are fully compensated for when lost. These results implicate that αsyn levels can be reduced in neurons without impairing (or improving) mitochondrial bioenergetics or distribution