ABSTRACT
To develop PET radiotracers for imaging of Alzheimer's disease, a new carbon-11 labeled potent and selective γ-secretase modulator (GSM) has been synthesized. The reference standard tetrahydrobenzisoxazole derivative 8 and its desmethylated precursor 9 were synthesized from cyclohex-2-en-1-one and 3-hydroxy-4-nitrobenzaldehyde in eight and nine steps with 11% and 5% overall chemical yield, respectively. The radiotracer [11C]8 was prepared from its corresponding precursor 9 with [11C]CH3OTf through O-11C-methylation and isolated by RP-HPLC combined with SPE in 45-50% radiochemical yield, based on [11C]CO2 and decay corrected to EOB. The radiochemical purity was >99%, and the molar activity (Am) at EOB was 555-740 GBq/µmol.
Subject(s)
Alzheimer Disease/diagnostic imaging , Amyloid Precursor Protein Secretases/metabolism , Carbon Radioisotopes/chemistry , Oxazoles/chemistry , Positron-Emission Tomography , Radiopharmaceuticals/chemistry , Alzheimer Disease/enzymology , Chromatography, Reverse-Phase , Humans , Solid Phase ExtractionABSTRACT
To develop PET tracers for imaging of Alzheimer's disease, new carbon-11 labeled potent and selective PDE5 inhibitors have been synthesized. The reference standards (5) and (12), and their corresponding desmethylated precursors (6) and (13) were synthesized from methyl 2-amino-5-bromobenzoate and (4-methoxyphenyl)methanamine in multiple steps with 2%, 1%, 1% and 0.2% overall chemical yield, respectively. The radiotracers ([11C]5) and ([11C]12) were prepared from their corresponding precursors 6 and 13 with [11C]CH3OTf through O-11C-methylation and isolated by HPLC combined with SPE in 40-50% radiochemical yield, based on [11C]CO2 and decay corrected to EOB. The radiochemical purity was >99%, and the molar activity (Am) at EOB was in a range of 370-740 GBq/µmol.
Subject(s)
Alzheimer Disease/diagnostic imaging , Carbon Radioisotopes/chemistry , Phosphodiesterase 5 Inhibitors/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Alzheimer Disease/enzymology , Chromatography, High Pressure Liquid , Chromatography, Reverse-Phase , Humans , Phosphodiesterase 5 Inhibitors/chemistry , Positron-Emission Tomography/methods , Radioligand Assay , Radiopharmaceuticals/chemistry , Vardenafil Dihydrochloride/analogs & derivatives , Vardenafil Dihydrochloride/chemical synthesis , Vardenafil Dihydrochloride/chemistryABSTRACT
To develop PET tracers for imaging of neuroinflammation, new carbon-11-labeled sEH/PDE4 dual inhibitors have been synthesized. The reference standard N-(4-methoxy-2-(trifluoromethyl)benzyl)benzamide (1) and its corresponding desmethylated precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)benzamide (2) were synthesized from (4-methoxy-2-(trifluoromethyl)phenyl)methanamine and benzoic acid in one and two steps with 84% and 49% overall chemical yield, respectively. The standard N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA, 4) and its precursor N-(4-hydroxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (5) were synthesized from methyl 4-piperidinecarboxylate, propionyl chloride and (4-methoxy-2-(trifluoromethyl)phenyl)methanamine in two and three steps with 62% and 34% overall chemical yield, respectively. The target tracers N-(4-[11C]methoxy-2-(trifluoromethyl)benzyl)benzamide ([11C]1) and N-(4-[11C]methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide ([11C]MPPA, [11C]4) were prepared from their corresponding precursors 2 and 5 with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 25-35% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (AM) at EOB was 370-740â¯GBq/µmol with a total synthesis time of 35-40-minutes from EOB.
Subject(s)
Carbon Radioisotopes/chemistry , Inflammation/drug therapy , Nervous System Diseases/drug therapy , Phosphodiesterase 4 Inhibitors/therapeutic use , Positron-Emission Tomography/methods , Humans , Phosphodiesterase 4 Inhibitors/pharmacologyABSTRACT
To develop PET tracers for imaging of Alzheimer's disease, a new carbon-11-labeled AMPAR allosteric modulator 4-cyclopropyl-7-(3-[11C]methoxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide ([11C]8) has been synthesized. The reference standard 4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (8) and its corresponding desmethylated precursor 4-cyclopropyl-7-(3-hydroxyphenoxy)-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (9) were synthesized from 4-methoxyabiline and chlorosulfonyl isocyanate in eight and nine steps with 3% and 1% overall chemical yield, respectively. The target tracer [11C]8 was prepared from the precursor 9 with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 10-15% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (AM) at EOB was 370-740â¯GBq/µmol with a total synthesis time of 35-40-minutes from EOB.
Subject(s)
Alzheimer Disease/diagnostic imaging , Radiopharmaceuticals/chemical synthesis , Allosteric Regulation , Carbon Radioisotopes/chemistry , Chromatography, High Pressure Liquid , Humans , Isotope Labeling , Positron-Emission Tomography , Radiopharmaceuticals/analysis , Radiopharmaceuticals/isolation & purification , Solid Phase Extraction , Thiadiazines/analysis , Thiadiazines/chemical synthesis , Thiadiazines/isolation & purificationABSTRACT
Carbon-11-labeled serotonin (5-hydroxytryptamine) 6 receptor (5-HT6R) antagonists, 1-[(2-bromophenyl)sulfonyl]-5-[11C]methoxy-3-[(4-methyl-1-piperazinyl)methyl]-1H-indole (O-[11C]2a) and 1-[(2-bromophenyl)sulfonyl]-5-methoxy-3-[(4-[11C]methyl-1-piperazinyl)methyl]-1H-indole (N-[11C]2a), 5-[11C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1-(phenylsulfonyl)-1H-indole (O-[11C]2b) and 5-methoxy-3-((4-[11C]methylpiperazin-1-yl)methyl)-1-(phenylsulfonyl)-1H-indole (N-[11C]2b), 1-((4-isopropylphenyl)sulfonyl)-5-[11C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (O-[11C]2c) and 1-((4-isopropylphenyl)sulfonyl)-5-methoxy-3-((4-[11C]methylpiperazin-1-yl)methyl)-1H-indole (N-[11C]2c), 1-((4-fluorophenyl)sulfonyl)-5-[11C]methoxy-3-((4-methylpiperazin-1-yl)methyl)-1H-indole (O-[11C]2d) and 1-((4-fluorophenyl)sulfonyl)-5-methoxy-3-((4-[11C]methylpiperazin-1-yl)methyl)-1H-indole (N-[11C]2d), were prepared from their O- or N-desmethylated precursors with [11C]CH3OTf through O- or N-[11C]methylation and isolated by HPLC combined with SPE in 40-50% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (MA) at EOB was 370-740â¯GBq/µmol with a total synthesis time of â¼40-min from EOB.
Subject(s)
Alzheimer Disease/diagnosis , Positron-Emission Tomography , Radiopharmaceuticals/chemical synthesis , Serotonin Antagonists/chemical synthesis , Alzheimer Disease/diagnostic imaging , Carbon Radioisotopes/chemistry , Humans , Indoles/chemistry , Isotope Labeling , Radiopharmaceuticals/chemistry , Receptors, Serotonin/chemistry , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemistryABSTRACT
The reference standard N-(3-(4-methylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (9) and its demethylated precursor N-(1-(5-methylpyridin-2-yl)-3-(piperazin-1-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide (8) were synthesized from pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and ethyl 2-cyanoacetate with overall chemical yield 13% in nine steps and 14% in eight steps, respectively. The target tracer N-(3-(4-[11C]methylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ([11C]9) was prepared from its precursor with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 50-60% radiochemical yield, based on [11C]CO2 and decay corrected to EOB. The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/µmol.
