RESUMEN
The purinergic P2X7 receptor (P2X7R) is an adenosine triphosphate (ATP) ligand-gated cationic channel receptor. P2X7R is closely associated with various inflammatory, immune, cancer, neurological, musculoskeletal and cardiovascular disorders. P2X7R is an interesting therapeutic target as well as molecular imaging target. This brief digest highlights the radioligands targeting P2X7R recently developed in drug discovery and molecular imaging agent development.
Asunto(s)
Sondas Moleculares/química , Radioisótopos/química , Receptores Purinérgicos P2X7/análisis , Animales , Descubrimiento de Drogas , Humanos , Marcaje Isotópico , Ligandos , Imagen Molecular , Tomografía de Emisión de Positrones , Receptores Purinérgicos P2X7/metabolismoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Radiofármacos/síntesis química , Regulación Alostérica , Radioisótopos de Carbono/química , Cromatografía Líquida de Alta Presión , Humanos , Marcaje Isotópico , Tomografía de Emisión de Positrones , Radiofármacos/análisis , Radiofármacos/aislamiento & purificación , Extracción en Fase Sólida , Tiadiazinas/análisis , Tiadiazinas/síntesis química , Tiadiazinas/aislamiento & purificaciónRESUMEN
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.
Asunto(s)
Radioisótopos de Carbono/química , Inflamación/tratamiento farmacológico , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Tomografía de Emisión de Positrones/métodos , Humanos , Inhibidores de Fosfodiesterasa 4/farmacologíaRESUMEN
The reference standards halo-GSK1482160 (F-, Br-, and I-) and their corresponding precursors desmethyl-halo-GSK1482160 (F-, Br-, and I-) were synthesized from (S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid or (S)-5-oxopyrrolidine-2-carboxylic acid and 2-halo-3-(trifluoromethyl)benzylamine (F-, Br-, and I-) in one step with 45-93% yields. The target tracers [11C]halo-GSK1482160 (F-, Br-, and I-) were prepared from desmethyl-halo-GSK1482160 (F-, Br-, and I-) with [11C]CH3OTf under basic conditions (NaOH-Na2CO3, solid, w/w 1:2) through N-[11C]methylation and isolated by HPLC combined with SPE in 40-50% decay corrected radiochemical yield. The radiochemical purity wasâ¯>99%, and the molar activity (AM) at end of bombardment (EOB) was 370-740â¯GBq/µmol. The potency of halo-GSK1482160 (F-, Br-, and I-) in comparison with GSK1482160 (Cl-) was determined by a radioligand competitive binding assay using [11C]GSK1482160, and the binding affinity Ki values for halo-GSK1482160 (F-, Br-, and I-) and GSK1482160 (Cl-) are 54.2, 2.5, 1.9 and 3.1â¯nM, respectively.
Asunto(s)
Ensayo de Unión Radioligante/métodos , Radiofármacos/síntesis química , HumanosRESUMEN
The reference standards methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate (5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-3-methoxybenzamide (5c), and their corresponding desmethylated precursors 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoic acid (6a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-3-hydroxybenzamide (6b), were synthesized from 5-amino-2,2-difluoro-1,3-benzodioxole and 3-substituted benzoic acids in 5 and 6 steps with 33% and 11%, 30% and 7% overall chemical yield, respectively. Carbon-11-labeled casein kinase 1 (CK1) inhibitors, [11C]methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate ([11C]5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]imidazol-6-yl)-3-[11C]methoxybenzamide ([11C]5c), were prepared from their O-desmethylated precursor 6a or 6b with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40-45% 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.
Asunto(s)
Bencimidazoles/síntesis química , Benzoatos/síntesis química , Quinasa de la Caseína I/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Radiofármacos/síntesis química , Enfermedad de Alzheimer/diagnóstico por imagen , Benzamidas/síntesis química , Benzamidas/química , Bencimidazoles/química , Benzoatos/química , Radioisótopos de Carbono , Interacciones Hidrofóbicas e Hidrofílicas , Tomografía de Emisión de Positrones , Inhibidores de Proteínas Quinasas/química , Radiofármacos/químicaRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Tomografía de Emisión de Positrones , Radiofármacos/síntesis química , Antagonistas de la Serotonina/síntesis química , Enfermedad de Alzheimer/diagnóstico por imagen , Radioisótopos de Carbono/química , Humanos , Indoles/química , Marcaje Isotópico , Radiofármacos/química , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/químicaRESUMEN
The reference standard IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from tert-butyl (S)-5-oxopyrrolidine-2-carboxylate, fluoroethylbromide, and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 12% in three steps. The target tracer [18F]IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-[18F]fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from desmethyl-GSK1482160 with 2-[18F]fluoroethyl tosylate, prepared from 1,2-ethylene glycol-bis-tosylate and K[18F]F/Kryptofix2.2.2, in two steps and isolated by HPLC combined with SPE in 1-3% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity at end of bombardment (EOB) was 74-370â¯GBq/µmol. The potency of IUR-1601 in comparison with GSK1482160 was determined by a radioligand competitive binding assay using [11C]GSK1482160, and the binding affinity Ki values for IUR-1601 and GSK1482160 are 4.31 and 5.14â¯nM, respectively.
Asunto(s)
Radiofármacos/química , Receptores Purinérgicos P2X7/química , Relación Dosis-Respuesta a Droga , Radioisótopos de Flúor , Humanos , Estructura Molecular , Ensayo de Unión Radioligante , Radiofármacos/síntesis química , Relación Estructura-ActividadRESUMEN
The authentic standards 2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide (4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-methoxyphenyl)pyridin-3-yl)isonicotinamide (7a), and their corresponding precursors 2-(cyclopropanecarboxamido)-N-(4-hydroxypyridin-3-yl)isonicotinamide (4b) and 2-(cyclopropanecarboxamido)-N-(4-(4-hydroxyphenyl)pyridin-3-yl)isonicotinamide (7b) were synthesized from methyl 2-aminoisonicotinate and cyclopropanecarbonyl chloride with overall chemical yield 47% in three steps, 22% in four steps, 40% in three steps, and 17% in four steps, respectively. The target tracers 2-(cyclopropanecarboxamido)-N-(4-[11C]methoxypyridin-3-yl)isonicotinamide ([11C]4a) and 2-(cyclopropanecarboxamido)-N-(4-(4-[11C]methoxyphenyl)pyridin-3-yl)isonicotinamide ([11C]7a) were prepared from the precursors (4b and 7b) 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 end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370-1110GBq/µmol with a total synthesis time of â¼40-min from EOB.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Glucógeno Sintasa Quinasa 3/metabolismo , Niacinamida/química , Tomografía de Emisión de Positrones , Radiofármacos/síntesis química , Radioisótopos de Carbono/química , Cromatografía Líquida de Alta Presión , Glucógeno Sintasa Quinasa 3/química , Humanos , Marcaje Isotópico , Niacinamida/síntesis química , Niacinamida/aislamiento & purificación , Radiofármacos/química , Radiofármacos/aislamiento & purificación , Extracción en Fase SólidaRESUMEN
The reference standard (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (HG-10-102-01) and its precursor (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-hydroxyphenyl)(morpholino)methanone (desmethyl-HG-10-102-01) were synthesized from 2,4,5-trichloropyrimide and 3-methoxy-4-nitrobenzoic acid with overall chemical yield 49% in four steps and 14% in five steps, respectively. The target tracer (4-((5-chloro-4-(methylamino)pyrimidin-2-yl)amino)-3-[11C]methoxyphenyl)(morpholino)methanone ([11C]HG-10-102-01) was prepared from the precursor desmethyl-HG-10-102-01 with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 45-55% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370-1110GBq/µmol with a total synthesis time of â¼40-min from EOB.
Asunto(s)
Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Enfermedad de Parkinson/enzimología , Tomografía de Emisión de Positrones , Pirimidinas/síntesis química , para-Aminobenzoatos/síntesis química , Humanos , RadiofármacosRESUMEN
The reference standard methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate (5) and its precursor 2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucine (6) were synthesized from 6-amino-2-mercaptopyrimidin-4-ol and BnBr with overall chemical yield 7% in five steps and 4% in six steps, respectively. The target tracer [11C]methyl (2-amino-5-(benzylthio)thiazolo[4,5-d]pyrimidin-7-yl)-d-leucinate ([11C]5) was prepared from the acid precursor 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 end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity (SA) at EOB was 370-1110GBq/µmol with a total synthesis time of â¼40-min from EOB. The radioligand depletion experiment of [11C]5 did not display specific binding to CX3CR1, and the competitive binding assay of ligand 5 found much lower CX3CR1 binding affinity.
Asunto(s)
Leucina/análogos & derivados , Pirimidinas/farmacología , Receptores de Quimiocina/antagonistas & inhibidores , Tiazoles/farmacología , Receptor 1 de Quimiocinas CX3C , Isótopos de Carbono , Relación Dosis-Respuesta a Droga , Humanos , Leucina/síntesis química , Leucina/química , Leucina/farmacología , Ligandos , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Receptores de Quimiocina/metabolismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
P2X4 receptor has become an interesting molecular target for treatment and PET imaging of neuroinflammation and associated brain diseases such as Alzheimer's disease. This study reports the first design, synthesis, radiolabeling and biological evaluation of new candidate PET P2X4 receptor radioligands using 5-BDBD, a specific P2X4 receptor antagonist, as a scaffold. 5-(3-Hydroxyphenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD analog, [11C]9) and 5-(3-Bromophenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD, [11C]8c) were prepared from their corresponding desmethylated precursors with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 30-50% decay corrected radiochemical yields with 370-1110GBq/µmol specific activity at EOB. 5-(3-[18F]Fluorophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]F-5-BDBD, [18F]5a) and 5-(3-(2-[18F]fluoroethoxy)phenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]FE-5-BDBD, [18F]11) were prepared from their corresponding nitro- and tosylated precursors by nucleophilic substitution with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC-SPE in 5-25% decay corrected radiochemical yields with 111-740GBq/µmol specific activity at EOB. The preliminary biological evaluation of radiolabeled 5-BDBD analogs indicated these new radioligands have similar biological activity with their parent compound 5-BDBD.
Asunto(s)
Azirinas/química , Dihidropiridinas/química , Radiofármacos/síntesis química , Receptores Purinérgicos P2X4/metabolismo , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Azirinas/síntesis química , Azirinas/metabolismo , Unión Competitiva , Radioisótopos de Carbono/química , Dihidropiridinas/síntesis química , Dihidropiridinas/metabolismo , Radioisótopos de Flúor/química , Células HEK293 , Humanos , Marcaje Isotópico , Tomografía de Emisión de Positrones , Unión Proteica , Radiofármacos/química , Radiofármacos/metabolismo , Receptores Purinérgicos P2X4/química , Receptores Purinérgicos P2X4/genética , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/químicaRESUMEN
The reference standard MK-1064 {5â³-chloro-N-((5,6-dimethoxypyridin-2-yl)methyl)-[2,2':5',3â³-terpyridine]-3'-carboxamide} was synthesized from methyl 2-chloro-5-iodonicotinate and 5-(chloropyridin-3-yl)boronic acid in 4 steps with 33% overall chemical yield. The precursor desmethyl-MK-1064 {5â³-chloro-N-((5-hydroxy-6-methoxypyridin-2-yl)methyl)-[2,2':5',3â³-terpyridine]-3'-carboxamide} for radiolabeling was synthesized from 2-bromopyridin-3-ol and 5â³-chloro-[2,2':5',3â³-terpyridine]-3'-carboxylic acid in 6 steps with 17% overall chemical yield. The target tracer [(11)C]MK-1064 {5â³-chloro-N-((5-[(11)C]methoxy-6-methoxypyridin-2-yl)methyl)-[2,2':5',3â³-terpyridine]-3'-carboxamide} was prepared by O-[(11)C]methylation of its corresponding precursor desmethyl-MK-1064 with [(11)C]CH3OTf under basic condition and isolated by a simplified solid-phase extraction (SPE) method in 50-60% decay corrected radiochemical yields based on [(11)C]CO2 at end of bombardment (EOB). The overall synthesis time from EOB was 23min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185-555GBq/µmol.
Asunto(s)
Receptores de Orexina/análisis , Tomografía de Emisión de Positrones , Ensayo de Unión Radioligante , Radiofármacos/química , Radioisótopos de Carbono , Humanos , Ligandos , Estructura Molecular , Radiofármacos/síntesis química , Radiofármacos/aislamiento & purificaciónRESUMEN
The target tracer carbon-11-labeled imidazopyridine- and purine-thioacetamide derivatives, N-(3-[(11)C]methoxy-4-methoxyphenyl)-2-((5-methoxy-3H-imidazo[4,5-b]pyridin-2-yl)thio)acetamide (3-[(11)C]4a) and N-(4-[(11)C]methoxy-3-methoxyphenyl)-2-((5-methoxy-3H-imidazo[4,5-b]pyridin-2-yl)thio)acetamide (4-[(11)C]4a); 2-((6-amino-9H-purin-8-yl)thio)-N-(3-[(11)C]methoxy-4-methoxyphenyl)acetamide (3-[(11)C]8a) and 2-((6-amino-9H-purin-8-yl)thio)-N-(4-[(11)C]methoxy-3-methoxyphenyl)acetamide (4-[(11)C]8a), were prepared by O-[(11)C]methylation of their corresponding precursors with [(11)C]CH3OTf under basic condition (2N NaOH) and isolated by a simplified solid-phase extraction (SPE) method in 50-60% radiochemical yields based on [(11)C]CO2 and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185-555GBq/µmol.
Asunto(s)
Imidazoles/química , Hidrolasas Diéster Fosfóricas/análisis , Tomografía de Emisión de Positrones , Purinas/química , Piridinas/química , Pirofosfatasas/análisis , Radiofármacos/síntesis química , Tioacetamida/química , Radioisótopos de Carbono , Humanos , Marcaje Isotópico , Estructura Molecular , Hidrolasas Diéster Fosfóricas/metabolismo , Pirofosfatasas/metabolismo , Trazadores Radiactivos , Radiofármacos/química , Radiofármacos/metabolismo , Extracción en Fase SólidaRESUMEN
The authentic standard PBB3 and its precursor N-desmethyl-PBB3 as well as TBS-protected N-desmethyl-PBB3 precursor for radiolabeling were synthesized from 5-bromo-2-nitropyridine, acrolein diethyl acetal, 6-methoxy-2-methylbenzothiazole, and diethylchlorophosphate with overall chemical yield 1% in six steps, 2% in five steps, and 1% in six steps, respectively. [(11)C]PBB3 was prepared from either desmethyl-PBB3 or TBS-protected desmethyl-PBB3 with [(11)C]CH3OTf through N-[(11)C]methylation and isolated by HPLC combined with SPE in 20-25% and 15-20% radiochemical yield, respectively, based on [(11)C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/µmol with a total synthesis time of ~40-min from EOB.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Aminopiridinas/química , Benzotiazoles/química , Tomografía de Emisión de Positrones , Proteínas tau/análisis , Aminopiridinas/síntesis química , Benzotiazoles/síntesis química , Radioisótopos de Carbono , Humanos , Imagen Molecular , Estructura MolecularRESUMEN
The authentic standard T807 and its nitro-precursor T807P as well as t-Boc-protected T807P precursor for radiolabeling were synthesized from (4-bromophenyl)boronic acid, 3-bromo-4-nitropyridine and 3-bromo-6-nitropyridine with overall chemical yield 27% in three steps, 4-7% in three to five steps, and 3-8% in four to five steps, respectively. [(18)F]T807 was synthesized from T807P by the nucleophilic [(18)F]fluorination with K[(18)F]F/Kryptofix 2.2.2 in DMSO at 140 °C followed by reduction with Fe powder/HCOOH through manual synthesis with 5-10% decay corrected radiochemical yield in two steps. [(18)F]T807 was also synthesized from t-Boc-protected T807P by a concurrent [(18)F]fluorination and deprotection with K[(18)F]F/Kryptofix 2.2.2 in DMSO at 140 °C and purified by HPLC-SPE method in a home-built automated [(18)F]radiosynthesis module with 20-30% decay corrected radiochemical yield in one step. The specific activity of [(18)F]T807 at end of bombardment (EOB) was 37-370 GBq/µmol.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Carbolinas/síntesis química , Técnicas de Química Sintética/métodos , Radioisótopos de Flúor/química , Radiofármacos/síntesis química , Proteínas tau/análisis , Carbolinas/química , Halogenación , Humanos , Tomografía de Emisión de Positrones , Radiofármacos/químicaRESUMEN
The reference standard CX-6258 {(E)-5-chloro-3-((5-(3-(4-methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one, 4a} and its desmethylated precursor N-desmethyl-CX-6258 {(E)-3-((5-(3-(1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)-5-chloroindolin-2-one, 5} for radiolabeling were synthesized from 5-bromo-2-furaldehyde and 3-carboxybenzeneboronic acid in 3 and 4 steps with 29-49% and 24-32% overall chemical yield, respectively. The target tracer [(11)C]CX-6258 {(E)-5-chloro-3-((5-(3-(4-[(11)C]methyl-1,4-diazepane-1-carbonyl)phenyl)furan-2-yl)methylene)indolin-2-one, [(11)C]4a} was prepared from N-desmethyl-CX-6258 (5) with [(11)C]CH3OTf under basic condition (2N NaOH) through N-[(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40-50% radiochemical yield based on [(11)C]CO2 and decay corrected to end of bombardment (EOB) with 370-1110GBq/µmol specific activity at EOB.
Asunto(s)
Azepinas/farmacología , Indoles/farmacología , Neoplasias/diagnóstico por imagen , Tomografía de Emisión de Positrones , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Radiofármacos/farmacología , Azepinas/síntesis química , Azepinas/química , Radioisótopos de Carbono , Cromatografía Líquida de Alta Presión , Humanos , Indoles/síntesis química , Indoles/química , Estructura Molecular , Neoplasias/enzimología , Radiofármacos/síntesis química , Radiofármacos/químicaRESUMEN
The authentic standards GSK1482160 and its isomer, as well as the radiolabeling precursors desmethyl-GSK1482160 and Boc-protected desmethyl-GSK1482160 were synthesized from L-pyroglutamic acid, methyl L-pyroglutamate and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 27-28% in 3 steps, 58% in 4 steps, 76% in 1 step and 33% in 2 steps, respectively. [(11)C]GSK1482160 was prepared from either desmethyl-GSK1482160 or Boc-protected desmethyl-GSK1482160 with [(11)C]CH3OTf through N-[(11)C]methylation and isolated by HPLC combined with SPE in 40-50% and 30-40% radiochemical yield, respectively, based on [(11)C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the specific activity at EOB was 370-1110 GBq/µmol with a total synthesis time of â¼40-min from EOB.
Asunto(s)
Tomografía de Emisión de Positrones , Ácido Pirrolidona Carboxílico/síntesis química , Ácido Pirrolidona Carboxílico/farmacología , Radiofármacos/farmacología , Receptores Purinérgicos P2X7/metabolismo , Radioisótopos de Carbono , Cromatografía Líquida de Alta Presión , Humanos , Imagen Molecular , Estructura Molecular , Ácido Pirrolidona Carboxílico/química , Radiofármacos/síntesis química , Radiofármacos/química , Extracción en Fase Sólida , Relación Estructura-ActividadRESUMEN
The reference standard 2-fluoro-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoic acid was synthesized from 2,5-dimethyl-2,5-hexanediol and 2-fluoro-4-methylbenzoic acid in 10 steps with 3% overall chemical yield. The precursor 2-nitro-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoic acid was synthesized from 2,5-dimethyl-2,5-hexanediol and dimethyl-2-nitroterephthalate in seven steps with 2% overall chemical yield. The target tracer 2-[(18)F]fluoro-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoic acid was synthesized from its nitro-precursor by the nucleophilic substitution with K[(18)F]F/Kryptofix 2.2.2 and isolated by HPLC combined with solid-phase extraction (SPE) purification in 20-30% radiochemical yield with 37-370GBq/µmol specific activity at end of bombardment (EOB).
Asunto(s)
Radioisótopos de Flúor/química , Tomografía de Emisión de Positrones , Radiofármacos , Receptores X Retinoide/análisis , Tetrahidronaftalenos , Animales , Bexaroteno , Humanos , Estructura Molecular , Radiofármacos/síntesis química , Radiofármacos/química , Tetrahidronaftalenos/síntesis química , Tetrahidronaftalenos/químicaRESUMEN
The authentic standard T808 and its corresponding mesylate precursor T808P were synthesized in six steps using ethyl vinyl ether and trichlorocetyl chloride as starting materials. The overall chemical yields of T808 and T808P were 35% and 52%, respectively. [(18)F]-T808 was synthesized from T808P by the nucleophilic substitution with K[(18)F]F/Kryptofix 2.2.2 and isolated by HPLC combined with solid-phase extraction (SPE) purification in 35-45% radiochemical yield with 37-370GBq/µmol specific activity at end of bombardment (EOB).
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/metabolismo , Bencimidazoles , Radioisótopos de Flúor , Tomografía de Emisión de Positrones , Pirimidinas , Proteínas tau/análisis , Bencimidazoles/síntesis química , Bencimidazoles/química , Radioisótopos de Flúor/química , Humanos , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Proteínas tau/metabolismoRESUMEN
The reference standards methyl 4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (10a), methyl 4-(2-methyl-5-(ethoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (10b) and corresponding precursors 4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (11a), methyl 4-(2-methyl-5-(ethoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (11b) were synthesized from methyl crotonate and 3-amino-4-methylbenzoic acid in multiple steps with moderate to excellent yields. The target tracer [(11)C]methyl 4-(2-methyl-5-(methoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate ([(11)C]10a) and [(11)C]methyl 4-(2-methyl-5-(ethoxycarbamoyl)phenylamino)-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate ([(11)C]10b) were prepared from their corresponding precursors with [(11)C]CH3OTf under basic condition through O-[(11)C]methylation and isolated by a simplified solid-phase extraction (SPE) method in 50-60% radiochemical yields at end of bombardment (EOB) with 185-555 GBq/µmol specific activity at end of synthesis (EOS).