Futureproofing [18F]Fludeoxyglucose manufacture at an Academic Medical Center

Abstract Background We recently upgraded our [18F]fludeoxyglucose (FDG) production capabilities with the goal of futureproofing our FDG clinical supply, expanding the number of batches of FDG we can manufacture each day, and improving patient throughput in our nuclear medicine clinic. In this paper we report upgrade of the synthesis modules to the GE FASTLab 2 platform (Phase 1) and cyclotron updates (Phase 2) from both practical and regulatory perspectives. We summarize our experience manufacturing FDG on the FASTLab 2 module with a high-yielding self-shielded niobium (Nb) fluorine-18 target. Results Following installation of Nb targets for production of fluorine-18, a 55 μA beam for 22 min generated 1330 ± 153 mCi of [18F]fluoride. Using these cyclotron beam parameters in combination with the FASTLab 2, activity yields (AY) of FDG were 957 ± 102 mCi at EOS, corresponding to 72% non-corrected AY (n = 235). Our workflow, inventory management and regulatory compliance have been greatly simplified following the synthesis module and cyclotron upgrades, and patient wait times for FDG PET have been cut in half at our nuclear medicine clinic. Conclusions The combination of FASTlab 2 and self-shielded Nb fluorine-18 targets have improved our yield of FDG, and enabled reliable and repeatable manufacture of the radiotracer for clinical use.https://deepblue.lib.umich.edu/bitstream/2027.42/145727/1/41181_2018_Article_48.pd

Development of Positron Emission Tomography Radiotracers for the GABA Transporter 1

In vivo positron emission tomography (PET) imaging of the γ-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radioligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure–activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter. Initial synthesis and rodent PET studies of N-[¹¹C]­methylnipecotic acid confirmed the low brain uptake of that small and polar molecule. The common design approach to improve blood–brain barrier permeability of GAT-1 inhibitors is the attachment of a large lipophilic substituent. We selected an unsymmetrical bis-aromatic residue attached to the ring nitrogen by a vinyl ether spacer from a series recently reported by Wanner and coworkers. Nucleophilic aromatic substitution of an aryl chloride precursor with [¹⁸F]­fluoride was used to prepare the desired candidate radiotracer (<i>R</i>,<i>E</i>/<i>Z</i>)-1-(2-((4-fluoro-2-(4-[¹⁸F]­fluorobenzoyl)­styryl)­oxy)­ethyl)­piperidine-3-carboxylic acid ((<i>R</i>,<i>E</i>/<i>Z</i>)-<b>[</b>^<b>18</b><b>F]­10</b>). PET studies in rats showed no brain uptake, which was not altered by pretreatment of animals with the P-glycoprotein inhibitor cyclosporine A, indicating efflux by Pgp was not responsible. Subsequent PET imaging studies of (<i>R</i>,<i>E</i>/<i>Z</i>)-[^<b>18</b><b>F]­10</b> in rhesus monkey brain showed very low brain uptake. Finally, to test if the free carboxylic acid group was the likely cause of poor brain uptake, PET studies were done using the ethyl ester derivative of (<i>R</i>,<i>E</i>/<i>Z</i>)-<b>[</b>^<b>18</b><b>F]­10</b>. Rapid and significant monkey brain uptake of the ester was observed, followed by a slow washout over 90 min. The blood–brain barrier permeability of the ester supports a hypothesis that the free acid function limits brain uptake of nipecotic acid-based GAT-1 radioligands, and future radiotracer efforts should investigate the use of carboxylic acid bioisosteres

Use of 55 PET radiotracers under approval of a Radioactive Drug Research Committee (RDRC)

Abstract Background In the US, EU and elsewhere, basic clinical research studies with positron emission tomography (PET) radiotracers that are generally recognized as safe and effective (GRASE) can often be conducted under institutional approval. For example, in the United States, such research is conducted under the oversight of a Radioactive Drug Research Committee (RDRC) as long as certain requirements are met. Firstly, the research must be for basic science and cannot be intended for immediate therapeutic or diagnostic purposes, or to determine the safety and effectiveness of the PET radiotracer. Secondly, the PET radiotracer must be generally recognized as safe and effective. Specifically, the mass dose to be administered must not cause any clinically detectable pharmacological effect in humans, and the radiation dose to be administered must be the smallest dose practical to perform the study and not exceed regulatory dose limits within a 1-year period. In our experience, the main barrier to using a PET radiotracer under RDRC approval is accessing the required information about mass and radioactive dosing. Results The University of Michigan (UM) has a long history of using PET radiotracers in clinical research studies. Herein we provide dosing information for 55 radiotracers that will enable other PET Centers to use them under the approval of their own RDRC committees. Conclusions The data provided herein will streamline future RDRC approval, and facilitate further basic science investigation of 55 PET radiotracers that target functionally relevant biomarkers in high impact disease states.http://deepblue.lib.umich.edu/bitstream/2027.42/174047/1/41181_2020_Article_110.pd

Validation of the collaborative outcomes study on health and functioning during infection times (COH-FIT) questionnaire for adults

Background. The Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT; www.coh-fit.com) is an anonymous and global online survey measuring health and functioning during COVID-19 pandemic. The aim of this study was to test concurrently the validity of COH-FIT items and the internal validity of the co-primary outcome, a composite psychopathology “P-score”. Methods. The COH-FIT survey has been translated into 30 languages (two blind forward-translations, consensus, one independent English back-translation, final harmonization). To measure mental health, 1-4 items (“COH-FIT items”) were extracted from validated questionnaires (e.g. Patient Health Questionnaire 9). COH-FIT items measured anxiety, depressive, post-traumatic, obsessive-compulsive, bipolar and psychotic symptoms, as well as stress, sleep and concentration. COH-FIT Items which correlated r≥0.5 with validated companion questionnaires, were initially retained. A P-score factor structure was then identified from these items using exploratory factor analysis (EFA) and confirmatory factor analyses (CFA) on data split into training and validation sets. Consistency of results across languages, gender and age was assessed. Results. From >150,000 adult responses by May 6th, 2022, a subset of 22,456 completed both COH-FIT items and validated questionnaires. Concurrent validity was consistently demonstrated across different languages for COH-FIT items. CFA confirmed EFA results of five first-order factors (anxiety, depression, post-traumatic, psychotic, psychophysiologic symptoms) and revealed a single second-order factor P-score, with high internal reliability (ω=0.95). Factor structure was consistent across age and sex. Conclusions. COH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health

Global and risk-group stratified well-being and mental health during the COVID-19 pandemic in adults: results from the international COH-FIT Study

International studies measuring wellbeing/multidimensional mental health before/ during the COVID-19 pandemic, including representative samples for >2 years, identifying risk groups and coping strategies are lacking. COH-FIT is an online, international, anonymous survey measuring changes in well-being (WHO-5) and a composite psychopathology P-score, and their associations with COVID-19 deaths/restrictions, 12 a-priori defined risk individual/cumulative factors, and coping strategies during COVID-19 pandemic (26/04/2020-26/06/2022) in 30 languages (representative, weighted non-representative, adults). T-test, χ2, penalized cubic splines, linear regression, correlation analyses were conducted. Analyzing 121,066/142,364 initiated surveys, WHO-5/P-score worsened intra-pandemic by 11.1±21.1/13.2±17.9 points (effect size d=0.50/0.60) (comparable results in representative/weighted non-probability samples). Persons with WHO-5 scores indicative of depression screening (2 years. The most subjectively effective coping strategies were exercise, internet use, social contacts. Identified risk groups, coping strategies and outcome trajectories can inform global public health strategies

Transverse momentum and pseudorapidity distributions of charged hadrons in pp collisions at (s)\sqrt(s) = 0.9 and 2.36 TeV

Measurements of inclusive charged-hadron transverse-momentum and pseudorapidity distributions are presented for proton-proton collisions at sqrt(s) = 0.9 and 2.36 TeV. The data were collected with the CMS detector during the LHC commissioning in December 2009. For non-single-diffractive interactions, the average charged-hadron transverse momentum is measured to be 0.46 +/- 0.01 (stat.) +/- 0.01 (syst.) GeV/c at 0.9 TeV and 0.50 +/- 0.01 (stat.) +/- 0.01 (syst.) GeV/c at 2.36 TeV, for pseudorapidities between -2.4 and +2.4. At these energies, the measured pseudorapidity densities in the central region, dN(charged)/d(eta) for |eta| < 0.5, are 3.48 +/- 0.02 (stat.) +/- 0.13 (syst.) and 4.47 +/- 0.04 (stat.) +/- 0.16 (syst.), respectively. The results at 0.9 TeV are in agreement with previous measurements and confirm the expectation of near equal hadron production in p-pbar and pp collisions. The results at 2.36 TeV represent the highest-energy measurements at a particle collider to date

Transverse-momentum and pseudorapidity distributions of charged hadrons in pppp collisions at s\sqrt{s} = 7 TeV

Charged-hadron transverse-momentum and pseudorapidity distributions in proton-proton collisions at $\sqrt{s} = 7$~TeV are measured with the inner tracking system of the CMS detector at the LHC. The charged-hadron yield is obtained by counting the number of reconstructed hits, hit-pairs, and fully reconstructed charged-particle tracks. The combination of the three methods gives a charged-particle multiplicity per unit of pseudorapidity \dnchdeta|_{|\eta| < 0.5} = 5.78\pm 0.01\stat\pm 0.23\syst for non-single-diffractive events, higher than predicted by commonly used models. The relative increase in charged-particle multiplicity from $\sqrt{s} = 0.9$ to 7~TeV is 66.1\%\pm 1.0\%\stat\pm 4.2\%\syst. The mean transverse momentum is measured to be 0.545\pm 0.005\stat\pm 0.015\syst\GeVc. The results are compared with similar measurements at lower energies.Charged-hadron transverse-momentum and pseudorapidity distributions in proton-proton collisions at sqrt(s) = 7 TeV are measured with the inner tracking system of the CMS detector at the LHC. The charged-hadron yield is obtained by counting the number of reconstructed hits, hit-pairs, and fully reconstructed charged-particle tracks. The combination of the three methods gives a charged-particle multiplicity per unit of pseudorapidity, dN(charged)/d(eta), for |eta| < 0.5, of 5.78 +/- 0.01 (stat) +/- 0.23 (syst) for non-single-diffractive events, higher than predicted by commonly used models. The relative increase in charged-particle multiplicity from sqrt(s) = 0.9 to 7 TeV is 66.1% +/- 1.0% (stat) +/- 4.2% (syst). The mean transverse momentum is measured to be 0.545 +/- 0.005 (stat) +/- 0.015 (syst) GeV/c. The results are compared with similar measurements at lower energies