| 1. |
- Bermejo Gómez, Antonio, et al.
(författare)
-
Efficient DBU accelerated synthesis of F-18-labelled trifluoroacetamides
- 2016
-
Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1359-7345 .- 1364-548X. ; 52:97, s. 13963-13966
-
Tidskriftsartikel (refereegranskat)abstract
- Nucleophilic F-18-fluorination of bromodifluoromethyl derivatives was performed using [F-18] Bu4NF in the presence of DBU(1,8-diazabicyclo[5.4.0]undec-7-ene). This novel procedure provided a diverse set of [F-18] trifluoroacetamides in good to excellent radiochemical conversions. A mechanism where DBU acts as organomediator in this transformation is proposed.
|
|
| 2. |
- Forsberg, Anton, et al.
(författare)
-
Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer's disease patients
- 2013
-
Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer-Verlag New York. - 1619-7070 .- 1619-7089. ; 40:4, s. 580-593
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer's disease (AD).METHODS: In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [(11)C]AZD2995 and [(11)C]AZD2184 in three healthy control subjects and seven AD patients.RESULTS: AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [(3)H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [(11)C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [(11)C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus.CONCLUSION: Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [(11)C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [(11)C]AZD2995. However, the very low nonspecific binding of [(11)C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy.
|
|
| 3. |
- Jahan, Mahabuba, et al.
(författare)
-
The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass.
- 2018
-
Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The G-protein-coupled receptor 44 (GPR44) is a beta cell-restricted target that may serve as a marker for beta cell mass (BCM) given the development of a suitable PET ligand.METHODS: The binding characteristics of the selected candidate, AZ12204657, at human GPR44 were determined using in vitro ligand binding assays. AZ12204657 was radiolabeled using 11C- or 3H-labeled methyl iodide ([11C/3H]CH3I) in one step, and the conversion of [11C/3H]CH3I to the radiolabeled product [11C/3H]AZ12204657 was quantitative. The specificity of radioligand binding to GPR44 and the selectivity for beta cells were evaluated by in vitro binding studies on pancreatic sections from human and non-human primates as well as on homogenates from endocrine and exocrine pancreatic compartments.RESULTS: The radiochemical purity of the resulting radioligand [11C]AZ12204657 was > 98%, with high molar activity (MA), 1351 ± 575 GBq/μmol (n = 18). The radiochemical purity of [3H]AZ12204657 was > 99% with MA of 2 GBq/μmol. Pancreatic binding of [11C/3H]AZ12204657 was co-localized with insulin-positive islets of Langerhans in non-diabetic individuals and individuals with type 2 diabetes (T2D). The binding of [11C]AZ12204657 to GPR44 was > 10 times higher in islet homogenates compared to exocrine homogenates. In human islets of Langerhans GPR44 was co-expressed with insulin, but not glucagon as assessed by co-staining and confocal microscopy.CONCLUSION: We radiolabeled [11C]AZ12204657, a potential PET radioligand for the beta cell-restricted protein GPR44. In vitro evaluation demonstrated that [3H]AZ12204657 and [11C]AZ12204657 selectively target pancreatic beta cells. [11C]AZ12204657 has promising properties as a marker for human BCM.
|
|
| 4. |
- Nag, Sangram, et al.
(författare)
-
Synthesis, Biodistribution, and Radiation Dosimetry of a Novel mGluR5 Radioligand : F-18-AZD9272
- 2020
-
Ingår i: ACS Chemical Neuroscience. - : AMER CHEMICAL SOC. - 1948-7193. ; 11:7, s. 1048-1057
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 5. |
- Schou, Magnus, et al.
(författare)
-
Pulmonary PET imaging confirms preferential lung target occupancy of an inhaled bronchodilator
- 2019
-
Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Positron emission tomography (PET) is a non-invasive molecular imaging technique that traces the distribution of radiolabeled molecules in experimental animals and human subjects. We hypothesized that PET could be used to visualize the binding of the bronchodilator drug ipratropium to muscarinic receptors (MR) in the lungs of living non-human primates (NHP). The objectives of this study were two-fold: (i) to develop a methodology for quantitative imaging of muscarinic receptors in NHP lung and (ii) to estimate and compare ipratropium-induced MR occupancy following drug administration via intravenous injection and inhalation, respectively.Methods: A series of PET measurements (n=18) was performed after intravenous injection of the selective muscarinic radioligand C-11-VC-002 in NHP (n=5). The lungs and pituitary gland (both rich in MR) were kept in the field of view. Each PET measurement was followed by a PET measurement preceded by treatment with ipratropium (intravenous or inhaled).Results: Radioligand binding was quantified using the Logan graphical analysis method providing the total volume of distribution (V-T). Ipratropium reduced the V-T in the lung and pituitary in a dose-dependent fashion. At similar plasma ipratropium concentrations, administration by inhalation produced larger reductions in V-T for the lungs. The plasma-derived apparent affinity for ipratropium binding in the lung was one order of magnitude higher after inhalation (K-iih=1.01nM) than after intravenous infusion (K-iiv=10.84nM).Conclusion: Quantitative muscarinic receptor occupancy imaging by PET articulates and quantifies the therapeutic advantage of the inhaled route of delivery and provides a tool for future developments of improved inhaled drugs.
|
|
