| 1. |
- Huttunen, Henri J., et al.
(author)
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Intraputamenal Cerebral Dopamine Neurotrophic Factor in Parkinson's Disease: A Randomized, Double-Blind, Multicenter Phase 1 Trial
- 2023
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In: Movement Disorders. - : John Wiley & Sons. - 0885-3185 .- 1531-8257. ; 38:7, s. 1209-1222
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Journal article (peer-reviewed)abstract
- Background: Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD). Objective: The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity. Methods: We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone-anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo-controlled, double-blind, 6-month main study followed by an active-treatment 6-month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [18F]FE-PE2I. Results: Drug-related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies. Conclusions: Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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| 2. |
- Kerstens, Vera S, et al.
(author)
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Reliability of dopamine transporter PET measurements with [18F]FE-PE2I in patients with Parkinson's disease.
- 2020
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In: EJNMMI Research. - : Springer Nature. - 2191-219X. ; 10:1
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Journal article (peer-reviewed)abstract
- BACKGROUND: Reliable quantification of dopamine transporter (DAT), a biomarker for Parkinson's disease (PD), is essential for diagnostic purposes as well as for evaluation of potential disease-modifying treatment. Due to degeneration of dopaminergic neurons and thus lower expected radioligand binding to DAT, higher measurement variability in PD patients might be expected than earlier reproducibility results in healthy controls. Therefore, we aimed to examine the test-retest properties of [18F]FE-PE2I-PET in PD patients.METHODS: Nine patients with PD (Hoehn and Yahr stage < 3) were included (men/women 6/3; mean age 65.2 ± 6.8 years). Each patient underwent two [18F]FE-PE2I-PET measurements within 7-28 days. The outcome measure was non-displaceable binding potential generated using wavelet-aided parametric imaging with cerebellum as reference region. We assessed test-retest performance using estimates of reliability and repeatability. Regions for primary analysis were caudate, putamen, ventral striatum, and substantia nigra. Exploratory analysis was performed for functional subdivisions of the striatum. We also compared the more vs. less affected side.RESULTS: [18F]FE-PE2I showed absolute variability estimates of 5.3-7.6% in striatal regions and 11% in substantia nigra and ICCs of 0.74-0.97 (median 0.91). The absolute variability for functional striatal subdivisions was 6.0-9.6% and ICCs of 0.76-0.91 (median 0.91). The less affected substantia nigra exhibited greater consistency than the more affected side. According to power calculations based on the current sample size, DAT changes of 5-11% in the striatum and 28% in the substantia nigra can be detected with a power of 0.8 (p < 0.0125).CONCLUSION: DAT-PET measurements with [18F]FE-PE2I in PD patients showed good repeatability and reliability. The slightly lower reliability in the substantia nigra in patients may be explained by lower DAT density and smaller anatomical size. Power calculations suggest that [18F]FE-PE2I PET is a suitable marker for longitudinal DAT decline in PD.TRIAL REGISTRATION: EudraCT 2017-003327-29.
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| 3. |
- Knudsen, Gitte M, et al.
(author)
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Guidelines for the content and format of PET brain data in publications and archives : A consensus paper
- 2020
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In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 40:8, s. 1576-1585
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Journal article (peer-reviewed)abstract
- It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.
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| 4. |
- Li, Junhao, et al.
(author)
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Exploring the Interactions between two Ligands, UCB-J and UCB-F, and Synaptic Vesicle Glycoprotein 2 Isoforms
- 2024
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In: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 15:10, s. 2018-2027
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Journal article (peer-reviewed)abstract
- In silico modeling was applied to study the efficiency of two ligands, namely, UCB-J and UCB-F, to bind to isoforms of the synaptic vesicle glycoprotein 2 (SV2) that are involved in the regulation of synaptic function in the nerve terminals, with the ultimate goal to understand the selectivity of the interaction between UCB-J and UCB-F to different isoforms of SV2. Docking and large-scale molecular dynamics simulations were carried out to unravel various binding patterns, types of interactions, and binding free energies, covering hydrogen bonding and nonspecific hydrophobic interactions, water bridge, π–π, and cation−π interactions. The overall preference for bonding types of UCB-J and UCB-F with particular residues in the protein pockets can be disclosed in detail. A unique interaction fingerprint, namely, hydrogen bonding with additional cation−π interaction with the pyridine moiety of UCB-J, could be established as an explanation for its high selectivity over the SV2 isoform A (SV2A). Other molecular details, primarily referring to the presence of π–π interactions and hydrogen bonding, could also be analyzed as sources of selectivity of the UCB-F tracer for the three isoforms. The simulations provide atomic details to support future development of new selective tracers targeting synaptic vesicle glycoproteins and their associated diseases.
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| 5. |
- Mallapura, Hemantha, et al.
(author)
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Advancements in Microfluidic Cassette-Based iMiDEVTM Technology for Production of L-[11C]Methionine and [11C]Choline
- 2024
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In: Pharmaceuticals. - : MDPI. - 1424-8247. ; 17:2
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Journal article (peer-reviewed)abstract
- Microfluidic technology is a highly efficient technique used in positron emission tomography (PET) radiochemical synthesis. This approach enables the precise control of reactant flows and reaction conditions, leading to improved yields and reduced synthesis time. The synthesis of two radiotracers, L-[11C]methionine and [11C]choline, was performed, using a microfluidic cassette and an iMiDEVTM module by employing a dose-on-demand approach for the synthesis process. We focused on optimizing the precursor amounts and radiosynthesis on the microfluidic cassette. L-[11C]methionine and [11C]choline were synthesized using a microreactor filled with a suitable resin for the radiochemical reaction. Trapping of the [11C]methyl iodide, its reaction, and solid-phase extraction purification were performed on a microreactor, achieving radiochemical yields of >80% for L-[11C]methionine and >60% for [11C]choline (n = 3). The total synthesis time for both the radiotracers was approximately 20 min. All quality control tests complied with the European Pharmacopeia standards. The dose-on-demand model allows for real-time adaptation to patient schedules, making it suitable for preclinical and clinical settings. Precursor optimization enhanced the cost efficiency without compromising the yield. The importance of dose-on-demand synthesis and optimized precursor utilization to produce L-[11C]methionine and [11C]choline was emphasized in this study. The results demonstrated the feasibility of dose-on-demand adaptations for clinical applications with reduced precursor quantities and high radiochemical yields.
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| 6. |
- Mallapura, Hemantha, et al.
(author)
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Microfluidic-based production of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC using the cassette-based iMiDEVâ„¢ microfluidic radiosynthesizer
- 2023
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In: EJNMMI Radiopharmacy and Chemistry. - : Springer. - 2365-421X. ; 8:1
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Journal article (peer-reviewed)abstract
- Background The demand for Ga-68-labeled radiotracers has significantly increased in the past decade, driven by the development of diversified imaging tracers, such as FAPI derivatives, PSMA-11, DOTA-TOC, and DOTA-TATE. These tracers have exhibited promising results in theranostic applications, fueling interest in exploring them for clinical use. Among these probes, Ga-68-labeled FAPI-46 and DOTA-TOC have emerged as key players due to their ability to diagnose a broad spectrum of cancers ([Ga-68]Ga-FAPI-46) in late-phase studies, whereas [Ga-68]Ga-DOTA-TOC is clinically approved for neuroendocrine tumors. To facilitate their production, we leveraged a microfluidic cassette-based iMiDEV radiosynthesizer, enabling the synthesis of [Ga-68]Ga-FAPI-46 and [Ga-68]Ga-DOTA-TOC based on a dose-on-demand (DOD) approach.Results Different mixing techniques were explored to influence radiochemical yield. We achieved decay-corrected yield of 44 +/- 5% for [Ga-68]Ga-FAPI-46 and 46 +/- 7% for [Ga-68]Ga-DOTA-TOC in approximately 30 min. The radiochemical purities (HPLC) of [Ga-68]Ga-FAPI-46 and [Ga-68]Ga-DOTA-TOC were 98.2 +/- 0.2% and 98.4 +/- 0.9%, respectively. All the quality control results complied with European Pharmacopoeia quality standards. We optimized various parameters, including Ga-68 trapping and elution, cassette batches, passive mixing in the reactor, and solid-phase extraction (SPE) purification and formulation. The developed synthesis method reduced the amount of precursor and other chemicals required for synthesis compared to conventional radiosynthesizers.Conclusions The microfluidic-based approach enabled the implementation of radiosynthesis of [Ga-68]Ga-FAPI-46 and [Ga-68]Ga-DOTA-TOC on the iMiDEV (TM) microfluidic module, paving the way for their use in preclinical and clinical applications. The microfluidic synthesis approach utilized 2-3 times less precursor than cassette-based conventional synthesis. The synthesis method was also successfully validated in a similar microfluidic iMiDEV module at a different research center for the synthesis of [Ga-68]Ga-FAPI-46 with limited runs. Our study demonstrated the potential of microfluidic methods for efficient and reliable radiometal-based radiopharmaceutical synthesis, contributing valuable insights for future advancements in this field and paving the way for routine clinical applications in the near future.
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| 7. |
- Mallapura, Hemantha, et al.
(author)
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Production of [C-11]Carbon Labelled Flumazenil and L-Deprenyl Using the iMiDEV (TM) Automated Microfluidic Radiosynthesizer
- 2022
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In: Molecules. - : MDPI. - 1431-5157 .- 1420-3049. ; 27:24
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Journal article (peer-reviewed)abstract
- In the last decade, microfluidic techniques have been explored in radiochemistry, and some of them have been implemented in preclinical production. However, these are not suitable and reliable for preparing different types of radiotracers or dose-on-demand production. A fully automated iMiDEV (TM) microfluidic radiosynthesizer has been introduced and this study is aimed at using of the iMiDEV (TM) radiosynthesizer with a microfluidic cassette to produce [C-11]flumazenil and [C-11]L-deprenyl. These two are known PET radioligands for benzodiazepine receptors and monoamine oxidase-B (MAO-B), respectively. Methods were successfully developed to produce [C-11]flumazenil and [C-11]L-deprenyl using [C-11]methyl iodide and [C-11]methyl triflate, respectively. The final products 1644 +/- 504 MBq (n = 7) and 533 +/- 20 MBq (n = 3) of [C-11]flumazenil and [C-11]L-deprenyl were produced with radiochemical purities were over 98% and the molar activity for [C-11]flumazenil and [C-11]L-deprenyl was 1912 +/- 552 GBq/mu mol, and 1463 +/- 439 GBq/mu mol, respectively, at the end of synthesis. All the QC tests complied with the European Pharmacopeia. Different parameters, such as solvents, bases, methylating agents, precursor concentration, and different batches of cassettes, were explored to increase the radiochemical yield. Synthesis methods were developed using 3-5 times less precursor than conventional methods. The fully automated iMiDEV (TM) microfluidic radiosynthesizer was successfully applied to prepare [C-11]flumazenil and [C-11]L-deprenyl.
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| 8. |
- Mattsson, Patrik, et al.
(author)
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High Contrast PET Imaging of Subcortical and Allocortical Amyloid-β in Early Alzheimer's Disease Using [11C]AZD2184
- 2024
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 98:4, s. 1391-1401
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Journal article (peer-reviewed)abstract
- BACKGROUND: Deposits of amyloid-β (Aβ) appear early in Alzheimer's disease (AD).OBJECTIVE: The aim of the present study was to compare the presence of cortical and subcortical Aβ in early AD using positron emission tomography (PET).METHODS: Eight cognitively unimpaired (CU) subjects, 8 with mild cognitive impairment (MCI) and 8 with mild AD were examined with PET and [11C]AZD2184. A data driven cut-point for Aβ positivity was defined by Gaussian mixture model of isocortex binding potential (BPND) values.RESULTS: Sixteen subjects (3 CU, 5 MCI and 8 AD) were Aβ-positive. BPND was lower in subcortical and allocortical regions compared to isocortex. Fifteen of the 16 Aβ-positive subjects displayed Aβ binding in striatum, 14 in thalamus and 10 in allocortical regions.CONCLUSIONS: Aβ deposits appear to be widespread in early AD. It cannot be excluded that deposits appear simultaneously throughout the whole brain which has implications for improved diagnostics and disease monitoring.
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| 9. |
- Nag, Sangram, et al.
(author)
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Synthesis, Biodistribution, and Radiation Dosimetry of a Novel mGluR5 Radioligand : F-18-AZD9272
- 2020
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In: ACS Chemical Neuroscience. - : AMER CHEMICAL SOC. - 1948-7193. ; 11:7, s. 1048-1057
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Journal article (peer-reviewed)abstract
- The metabotropic glutamate receptor subtype mGluR5 has been proposed as a potential drug target for CNS disorders such as anxiety, depression, Parkinson's disease, and epilepsy. The AstraZeneca compound AZD9272 has previously been labeled with carbon-11 and used as a PET radioligand for mGluR5 receptor binding. The molecular structure of AZD9272 allows one to label the molecule with fluorine-18 without altering the structure. The aim of this study was to develop a fluorine-18 analogue of AZD9272 and to examine its binding distribution in the nonhuman primate brain in vivo as well as to obtain whole body radiation dosimetry. F-18-AZD9272 was successfully synthesized from a nitro precursor. The radioligand was stable, with a radiochemical purity of >99% at 2 h after formulation in a sterile phosphate buffered solution (pH = 7.4). After injection of F-18-AZD9272 in two cynomolgus monkeys, the maximum whole brain radioactivity concentration was 4.9-6.7% of the injected dose (n = 2) and PET images showed a pattern of regional radioactivity consistent with that previously obtained for C-11-AZD9272. The percentage of parent radioligand in plasma was 59 and 64% (n = 2) at 120 min after injection of F-18-AZD9272, consistent with high metabolic stability. Two whole body PET scans were performed in nonhuman primates for a total of 231 min after injection of F-18-AZD9272. Highest uptakes were seen in liver and small intestine, followed by brain and kidney. The estimated effective dose was around 0.017 mSv/MBq. F-18-AZD9272 shows suitable properties as a PET radioligand for in vivo imaging of binding in the primate brain. F-18-labeled AZD9272 offers advantages over C-11-AZD9272 in terms of higher image resolution, combined with a longer half-life. Moreover, based on the distribution and the estimated radiation burden, imaging of F-18-AZD9272 could be used as an improved tool for quantitative assessment and characterization of AZD9272 binding sites in the human brain by using PET.
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| 10. |
- Ovdiichuk, Olga, et al.
(author)
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Implementation of iMiDEV™, a new fully automated microfluidic platform for radiopharmaceutical production
- 2021
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In: Lab on a Chip. - : Royal Society of Chemistry. - 1473-0197 .- 1473-0189. ; 21:11, s. 2272-2282
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Journal article (peer-reviewed)abstract
- iMiDEV™ microfluidic system is a new automated tool for a small-scale production of radiopharmaceuticals. This new radiochemistry module utilizes microfluidic cassettes capable of producing diversified radiopharmaceuticals in liquid phase reactions in an automated synthesizer. The user interface is intuitive and designed to give the operator all the information required and to allow driving the synthesis either manually or fully automatically. In this work, we have demonstrated liquid phase reaction and presented the first results of an efficient fully automated [18F]NaF radiosynthesis on the iMiDEV™ platform. Different parameters such as a type of cyclotron targets, initial activity, concentration and volume of the fluoride-18 targetry have been investigated in order to elaborate the optimised radiolabelling of the ligand. Single and double sodium [18F]fluoride synthesis procedures have been successfully developed using two chambers of the cassette. A single-dose of radiotracer was produced in an average radiochemical yield of 87% (decay corrected) within 8 min and quality control tests were performed as per European Pharmacopoeia.
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