~(18)F标记的白藜芦醇衍生物的合成及作为β-淀粉样斑块显像剂的初步评价
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摘要
设计并合成四种白藜芦醇衍生物,以评价其用于Aβ-斑块PET显像的可能性。通过化学合成得到四种白藜芦醇衍生物的前体化合物和参比化合物;使用参比化合物测定其与Aβ1-42蛋白聚集体的体外结合性;经[~(18)F]亲核取代反应对具有较高亲和力的化合物进行放化标记,并进行体外稳定性、脂水分配系数、生物分布等的测定。体外竞争结合实验显示化合物(E)-1-(3,5-二甲氧基苯乙烯基)-4-(2-(2-(2-氟乙氧基)乙氧基)乙氧基)苯([~(19)F]F-7)具有中度的结合性(Ki=43.76nmol/L);[~(18)F]F-7的标记时间为32min,放化产率(未校正)为(23±2)%,经SEP PAK C18柱纯化后放化纯度大于95%,且在生理盐水中的稳定性大于3h,具有较好的脂溶性(lg P=3.08);生物分布实验显示化合物[~(18)F]F-7具有较快的脑清除,注射后2min和60min的脑摄取分别为(0.55±0.05)%ID/g和(0.06±0.01)%ID/g,清除比达到9。化合物[~(18)F]F-7是一种潜在的β-淀粉样斑块PET显像剂。
In this study,four fluorine-substituted resveratrol derivatives were designed and synthesized as candidates forβ-amyloid(Aβ)plaque imaging.The in vitro binding studies using Aβ1-42 peptide aggregates were carried out with the four resveratrol derivatives.The F-18 labeled derivatives with the highest binding affinities to Aβ_(1-42) aggregates were prepared using the appropriate mesylate precursors in DMSO,and the stability and partition coeffi-cient were also evaluated.And the biodistribution studies were performed using the normal Kunming mice.Among all derivatives examined,(E)-1-(3,5-dimethoxystyryl)-4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)benzene(Compound 7)shows highest binding affinity to Aβ_(1-42)-peptide aggregates(Ki=43.76nmol/L,with[~(125)I]IMPY as radioligand).No-carrieradded[~(18)F]F-7was successfully prepared within 32min(uncorrected yield(23±2)%)and purified using a Sep Pak C18 cartridge with a high radiochemical purity(>95%).[~(18)F]F-7shows a good stability in saline and an adequate lipophilicity(lg P=3.08).For biodistribution,[~(18)F]F-7displays moderate initial brain uptake((0.55±0.05)%ID/g at 2min)with rapid wash-out from brains((0.06±0.01)%ID/g at 60min);2-to-60 min uptake ratio is 9.Of these compounds,[~(19)F]F-7shows the highest binding affinity,and [18 F]F-7exhibits suitable lipophilicity and reasonable initial brain uptake and fast washout.All these results indicate that[~(18)F]F-7is a suitable radioligand for Aβplaque imaging.
In this study,four fluorine-substituted resveratrol derivatives were designed and synthesized as candidates forβ-amyloid(Aβ)plaque imaging.The in vitro binding studies using Aβ1-42 peptide aggregates were carried out with the four resveratrol derivatives.The F-18 labeled derivatives with the highest binding affinities to Aβ_(1-42) aggregates were prepared using the appropriate mesylate precursors in DMSO,and the stability and partition coeffi-cient were also evaluated.And the biodistribution studies were performed using the normal Kunming mice.Among all derivatives examined,(E)-1-(3,5-dimethoxystyryl)-4-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)benzene(Compound 7)shows highest binding affinity to Aβ_(1-42)-peptide aggregates(Ki=43.76nmol/L,with[~(125)I]IMPY as radioligand).No-carrieradded[~(18)F]F-7was successfully prepared within 32min(uncorrected yield(23±2)%)and purified using a Sep Pak C18 cartridge with a high radiochemical purity(>95%).[~(18)F]F-7shows a good stability in saline and an adequate lipophilicity(lg P=3.08).For biodistribution,[~(18)F]F-7displays moderate initial brain uptake((0.55±0.05)%ID/g at 2min)with rapid wash-out from brains((0.06±0.01)%ID/g at 60min);2-to-60 min uptake ratio is 9.Of these compounds,[~(19)F]F-7shows the highest binding affinity,and [18 F]F-7exhibits suitable lipophilicity and reasonable initial brain uptake and fast washout.All these results indicate that[~(18)F]F-7is a suitable radioligand for Aβplaque imaging.
引文
[1]Bastianetto S,Brouillette J,Quirion R.Neuroprotective effects of natural products:interaction with intracellular kinases,amyloid peptides and a possible role for transthyretin[J].Neurochem Res,2007,32(10):1720-1725.
[2]Rivière C,Richard T,Quentin L,et al.Inhibitory activity of stilbenes on Alzheimer’s beta-amyloid fibrils in vitro[J].Bioorg Med Chem,2007,15(2):1160-1167.
[3]Riviere C,Richard T,Vitrac X,et al.New polyphenols active on beta-amyloid aggregation[J].Bioorg Med Chem Lett,2008,18:828-831.
[4]Marambaud P,Zhao H,Davies P.Resveratrol promotes clearance of Alzheimer’s disease amyloid-βpeptides[J].J Biol Chem,2005,280:37377-37382.
[5]Han Y S,Zheng W H,Bastianetto S,et al.Neuroprotective effects of resveratrol againstβ-amyloidinduced neurotoxicity in rat hippocampal neurons:involvement of protein kinase C[J].Br J Pharmacol,2004,141:997-1005.
[6]Ahn J S,Lee J H,Kim J H,et al.Novel method for quantitative determination of amyloid fibrils of alpha-synuclein and amyloid beta/A4 protein by using resveratrol[J].Anal Biochem,2007,367:259-265.
[7]Kamal R,Chadha V D,Dhawan D K.Bio-evaluation of 99mTc resveratrol in targeting chemically induced mammary tumors in rats[J].Austin J Nucl Med Radiother,2014,1(1):4.
[8]Kamal R,Dhawan D K,Chadha V D.Evaluation of99mTc-resveratrol as a colon cancer targeting probe[J].Eur J Cancer Care(Engl),2016,doi:10.1111/ecc.12504.[Epub ahead of print].
[9]Chen X J.QSAR and primary docking studies of trans-stilbene(TSB)series of imaging agents for b-amyloid plaques[J].J Mol Struct:Theochem,2006,763:83-89.
[10]Mathis C A,Wang Y,Klunk W E.Imagingβ-amyloid plaques and neurofibrillary tangles in the aging human brain[J].Current Pharmaceutical Design,2004,10:1469-1492.
[11]Verhoeff N P,Wilson A A,Takeshita S,et al.Invivoimaging of Alzheimer disease beta-amyloid with[11 C]-SB-13PET[J].Am J Geriatr Psych,2004,12:584-595.
[12]Rowe C C,Ackerman U,Browne W,et al.Imaging of amyloidβin Alzheimer’s disease with 18FBAY94-9172,a novel PET tracer:proof of mechanism[J].Lancet Neurol,2008,7:129-135.
[13]Lee I,Choe Y S,Choi J Y,et al.Synthesis and evaluation of 18F-labeled styryltriazole and resveratrol derivatives forβ-amyloid plaque imaging[J].J Med Chem,2012,55(2):883-892.
[14]陈祥纪.β-淀粉样斑块显像剂的研究[J].化学进展,2007,19:123-129.
[15]Wang H,Shi H,Yu H,et al.Facile and rapid onestep radiosynthesis of[18F]BAY94-9172with a new precursor[J].Nucl Med Biol,2011,38(1):121-127.
[16]Cui M,Ono M,Kimura H,et al.Novel 18F-labeled benzoxazole derivativesas potential positron emission tomography probes for imaging of cerebralβ-amyloid plaques in Alzheimer’s disease[J].J Med Chem,2012,55:9136-9145.
[17]Zhang W,Oya S,Kung M P,et al.F-18polyethyleneglycol stilbenes as PET imaging agents targeting Aβaggregates in the brain[J].Nucl Med Biol,2005,32:799-809.
[18]史旭东,王晓,申一鸣,等.超顺磁性氧化铁纳米粒子SPION-dopa-PEG-DOTA/RGD的64 Cu标记、纯化及生物分布[J].核化学与放射化学,2015,37(8):250-256.
[19]Imando A M,Cuendet M,Desmarchelier C,et al.Cancer chemopreventive and antioxidant activities of pterostilbene,a naturally occurring analogue of resveratrol[J].J Agric Food Chem,2002,50:3453-3457.
[20]Liu Y,Zhu L,Pl9ssl K,et al.Optimization of automated radiosynthesis of[18 F]AV-45:a new PET imaging agent for Alzheimer’s disease[J].Nucl Med Biol,2010,37(8):917-925.
[21]Wang H,Hu K,Tang G,et al.Simple and efficient automated radiosynthesis of 2-18 F-fluoropropionic acid using solid-phase extraction cartridges purification[J].J Labelled Compd Radiopharm,2012,55:366-370.
[2]Rivière C,Richard T,Quentin L,et al.Inhibitory activity of stilbenes on Alzheimer’s beta-amyloid fibrils in vitro[J].Bioorg Med Chem,2007,15(2):1160-1167.
[3]Riviere C,Richard T,Vitrac X,et al.New polyphenols active on beta-amyloid aggregation[J].Bioorg Med Chem Lett,2008,18:828-831.
[4]Marambaud P,Zhao H,Davies P.Resveratrol promotes clearance of Alzheimer’s disease amyloid-βpeptides[J].J Biol Chem,2005,280:37377-37382.
[5]Han Y S,Zheng W H,Bastianetto S,et al.Neuroprotective effects of resveratrol againstβ-amyloidinduced neurotoxicity in rat hippocampal neurons:involvement of protein kinase C[J].Br J Pharmacol,2004,141:997-1005.
[6]Ahn J S,Lee J H,Kim J H,et al.Novel method for quantitative determination of amyloid fibrils of alpha-synuclein and amyloid beta/A4 protein by using resveratrol[J].Anal Biochem,2007,367:259-265.
[7]Kamal R,Chadha V D,Dhawan D K.Bio-evaluation of 99mTc resveratrol in targeting chemically induced mammary tumors in rats[J].Austin J Nucl Med Radiother,2014,1(1):4.
[8]Kamal R,Dhawan D K,Chadha V D.Evaluation of99mTc-resveratrol as a colon cancer targeting probe[J].Eur J Cancer Care(Engl),2016,doi:10.1111/ecc.12504.[Epub ahead of print].
[9]Chen X J.QSAR and primary docking studies of trans-stilbene(TSB)series of imaging agents for b-amyloid plaques[J].J Mol Struct:Theochem,2006,763:83-89.
[10]Mathis C A,Wang Y,Klunk W E.Imagingβ-amyloid plaques and neurofibrillary tangles in the aging human brain[J].Current Pharmaceutical Design,2004,10:1469-1492.
[11]Verhoeff N P,Wilson A A,Takeshita S,et al.Invivoimaging of Alzheimer disease beta-amyloid with[11 C]-SB-13PET[J].Am J Geriatr Psych,2004,12:584-595.
[12]Rowe C C,Ackerman U,Browne W,et al.Imaging of amyloidβin Alzheimer’s disease with 18FBAY94-9172,a novel PET tracer:proof of mechanism[J].Lancet Neurol,2008,7:129-135.
[13]Lee I,Choe Y S,Choi J Y,et al.Synthesis and evaluation of 18F-labeled styryltriazole and resveratrol derivatives forβ-amyloid plaque imaging[J].J Med Chem,2012,55(2):883-892.
[14]陈祥纪.β-淀粉样斑块显像剂的研究[J].化学进展,2007,19:123-129.
[15]Wang H,Shi H,Yu H,et al.Facile and rapid onestep radiosynthesis of[18F]BAY94-9172with a new precursor[J].Nucl Med Biol,2011,38(1):121-127.
[16]Cui M,Ono M,Kimura H,et al.Novel 18F-labeled benzoxazole derivativesas potential positron emission tomography probes for imaging of cerebralβ-amyloid plaques in Alzheimer’s disease[J].J Med Chem,2012,55:9136-9145.
[17]Zhang W,Oya S,Kung M P,et al.F-18polyethyleneglycol stilbenes as PET imaging agents targeting Aβaggregates in the brain[J].Nucl Med Biol,2005,32:799-809.
[18]史旭东,王晓,申一鸣,等.超顺磁性氧化铁纳米粒子SPION-dopa-PEG-DOTA/RGD的64 Cu标记、纯化及生物分布[J].核化学与放射化学,2015,37(8):250-256.
[19]Imando A M,Cuendet M,Desmarchelier C,et al.Cancer chemopreventive and antioxidant activities of pterostilbene,a naturally occurring analogue of resveratrol[J].J Agric Food Chem,2002,50:3453-3457.
[20]Liu Y,Zhu L,Pl9ssl K,et al.Optimization of automated radiosynthesis of[18 F]AV-45:a new PET imaging agent for Alzheimer’s disease[J].Nucl Med Biol,2010,37(8):917-925.
[21]Wang H,Hu K,Tang G,et al.Simple and efficient automated radiosynthesis of 2-18 F-fluoropropionic acid using solid-phase extraction cartridges purification[J].J Labelled Compd Radiopharm,2012,55:366-370.