Radioligands for the study of brain 5-HT1A receptors in vivo–development of some new analogues of way
Victor W. PikeChrister HalldinHåkan WikströmSandrine MarchaisJulie A. McCarronJohan SandellBartek NowickiCarl-Gunnar SwahnSafiye OsmanSusan P. HumeM. ConstantinouBengt AndréeLars Farde
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Radioligand
Human brain
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Spect imaging
PET Imaging
VEGFR2 is one of the best characterized VEGF receptors and mediates the stimulating effect of VEGF on proliferation, migration and survival of nerve cells of different types, like microglia, astrocytes and neuronal stem cells. Altered expression of VEGFR2 is reported in the pathology of neurological, neuropsychiatric, brain malignancies and developmental disorders. PET imaging that allows for in vivo visualization of specific targets on the molecular level allows early detection, diagnosis and treatment monitoring non-invasively and accelerates therapeutic development. Our ongoing effort to derive a PET tracer that can be used to quantify the changes in VEGFR2 and resulted in the identification of N -(benzo furan-5-yl)- N -2,6-trimethylfuro[2,3-d]pyrimidin-4-amine (BTFP) (IC 50 = 5.8 nM). In this report, the automated radiochemical synthesis and in vivo evaluation of a high affinity VEGFR2 ligand, [ 11 C]BTFP by using PET is described. [ 11 C]BTFP is synthesized in 35±5% radiochemical yield by radiomethylating the N -desmethyl-BTFP precursor using [ 11 C]CH 3 I. MicroPET studies in mice indicated a blood-brain barrier penetration of [ 11 C]BTFP, with modest uptake and specific binding. Although, the low brain uptake of [ 11 C]BTFP diminished its utility for in vivo imaging application, it can be used as a lead molecule for developing new PET tracers for central nervous system imaging.
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[18 F]FTC-146 was introduced as a very potent and selective sigma-1 receptor radioligand, which has shown promising application as an imaging agent for neuropathic pain with positron emission tomography. In line with a multi-laboratory project on animal welfare, we chose this radioligand to investigate its potential for detecting neuropathic pain and tissue damage in tumor-bearing animals. However, the radiochemical yield (RCY) of around 4-7% was not satisfactory to us, and efforts were made to improve it. Herein, we describe an improved approach for the radiosynthesis of [18 F]FTC-146 resulting in a RCY, which is sevenfold higher than that previously reported. A tosylate precursor was synthesized and radio-fluorination experiments were performed via aliphatic nucleophilic substitution reactions using either K[18 F]F-Kryptofix®222 (K2.2.2 )-carbonate system or tetra-n-butylammonium [18 F]fluoride ([18 F]TBAF). Several parameters affecting the radiolabeling reaction such as solvent, 18 F-fluorination agent with the corresponding amount of base, labeling time, and temperature were investigated. Best labeling reaction conditions were found to be [18 F]TBAF and acetonitrile as solvent at 100°C. The new protocol was then translated to an automated procedure using a FX2 N synthesis module. Finally, the radiotracer reproducibly obtained with RCYs of 41.7 ± 4.4% in high radiochemical purity (>98%) and molar activities up to 171 GBq/μmol.
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Compound 1 is a selective and potent agonist of the G protein-coupled receptor GPR139 (EC50 = 39 nM).
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Since to date very limited information on the distribution and function of the adenosine A 3 receptor is available, the development of a suitable radioligand is needed. Such a selective radioligand can then be used for quantitative autoradiography, preclinical studies in animals and subsequent human PET applications. Recently, a promising candidate compound, 5-(2-fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (FE@SUPPY), has been presented. The successful preparation of a suitable labelling precursor and the evaluation and optimization of the radiosynthesis of [ 18 F] FE@SUPPY is presented herewith. For satisfactory yields, a reaction temperature of 75 °C has to be applied for at least 20 min using 8–10 mg of precursor. Until now, 15 complete high-scale radiosyntheses were performed. Starting from an average of 51±12 GBq (average ±SD; range: 30–67 GBq) [ 18 F]fluoride, 9.4–3.6 GBq of formulated [ 18 F]FE@SUPPY (32.3±12.4%, based on [ 18 F]fluoride, corrected for decay) were prepared in <105 min.
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