Poly(ADP-ribose)polymerase 1(PARP1)is a multifunctional protein involved in diverse cellular functions,notably DNA damage repair.Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies.Des...Poly(ADP-ribose)polymerase 1(PARP1)is a multifunctional protein involved in diverse cellular functions,notably DNA damage repair.Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies.Despite the increased use of PARP inhibitors,challenges persist in achieving PARP1 selectivity and effective blood-brain barrier(BBB)penetration.The development of a PARP1-specific positron emission tomography(PET)radioligand is crucial for understanding disease biology and performing target occupancy studies,which may aid in the development of PARP1-specific inhibitors.In this study,we leverage the recently identified PARP1 inhibitor,AZD9574,to introduce the design and development of its ^(18)F-isotopologue([^(18)F]AZD9574).Our comprehensive approach,encompassing pharmacological,cellular,autoradiographic,and in vivo PET imaging evaluations in non-human primates,demonstrates the capacity of[^(18)F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB.These findings position[^(18)F]AZD9574 as a viable molecular imaging tool,poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.展开更多
Monoacylglycerol lipase(MAGL)constitutes a crucial serine hydrolase within the endocannabinoid system,which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders...Monoacylglycerol lipase(MAGL)constitutes a crucial serine hydrolase within the endocannabinoid system,which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders.While MAGL inhibitors have entered the clinical arena,a highly selective and MAGL-specific positron emission tomography(PET)ligand holds promise to significantly facilitate clinical drug development by allowing the quantification of MAGL levels and the assessment of target occupancy in patients.Accordingly,this study aimed to develop a new series of reversible MAGL inhibitor candidates,based on a piperazinyl azetidine diamide scaffold.Compound 3 demonstrated the most promising performance characteristics in pharmacological evaluations compared to other MAGL inhibitor candidates.Subsequently,it was labeled with fluorine-18 and further assessed through autoradiography and PET imaging,as well as ex vivo biodistribution and metabolite analysis experiments in rodents.Compound 3 exhibited a heterogeneous radioactivity distribution,favorable brain uptake,and excellent in vivo binding specificity.Target occupancy studies with a therapeutic MAGL inhibitor demonstrated a dose-dependent PET signal reduction of[^(18)F]3 in rat brains.In conclusion,[^(18)F]3([^(18)F]MAGL-2011)has the potential to serve as an effective MAGL PET ligand.展开更多
基金Steven H.Liang gratefully acknowledges the support provided,in part,by Emory Radiology Chair Fund and Emory School of Medicine Endowed Directorship(USA)James B.Daunais acknowledges the NIH grant support U01AA014106 and AA028007(USA)Jimmy S.Patel is the recipient of NCI cancer biology postdoctoral fellowship(T32CA275777,USA).
文摘Poly(ADP-ribose)polymerase 1(PARP1)is a multifunctional protein involved in diverse cellular functions,notably DNA damage repair.Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies.Despite the increased use of PARP inhibitors,challenges persist in achieving PARP1 selectivity and effective blood-brain barrier(BBB)penetration.The development of a PARP1-specific positron emission tomography(PET)radioligand is crucial for understanding disease biology and performing target occupancy studies,which may aid in the development of PARP1-specific inhibitors.In this study,we leverage the recently identified PARP1 inhibitor,AZD9574,to introduce the design and development of its ^(18)F-isotopologue([^(18)F]AZD9574).Our comprehensive approach,encompassing pharmacological,cellular,autoradiographic,and in vivo PET imaging evaluations in non-human primates,demonstrates the capacity of[^(18)F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB.These findings position[^(18)F]AZD9574 as a viable molecular imaging tool,poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.
基金supported by NCI T32CA275777support provided,in part,by the NIH grants(S10OD034326,DA038000 and DA043507,USA)+1 种基金Emory Radiology Startup and Chair FundEmory School of Medicine Endowed Directorship.
文摘Monoacylglycerol lipase(MAGL)constitutes a crucial serine hydrolase within the endocannabinoid system,which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders.While MAGL inhibitors have entered the clinical arena,a highly selective and MAGL-specific positron emission tomography(PET)ligand holds promise to significantly facilitate clinical drug development by allowing the quantification of MAGL levels and the assessment of target occupancy in patients.Accordingly,this study aimed to develop a new series of reversible MAGL inhibitor candidates,based on a piperazinyl azetidine diamide scaffold.Compound 3 demonstrated the most promising performance characteristics in pharmacological evaluations compared to other MAGL inhibitor candidates.Subsequently,it was labeled with fluorine-18 and further assessed through autoradiography and PET imaging,as well as ex vivo biodistribution and metabolite analysis experiments in rodents.Compound 3 exhibited a heterogeneous radioactivity distribution,favorable brain uptake,and excellent in vivo binding specificity.Target occupancy studies with a therapeutic MAGL inhibitor demonstrated a dose-dependent PET signal reduction of[^(18)F]3 in rat brains.In conclusion,[^(18)F]3([^(18)F]MAGL-2011)has the potential to serve as an effective MAGL PET ligand.
