A first-in-human study of 11C-MTP38, a novel PET ligand for phosphodiesterase 7

Purpose Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand 11 C-MTP38, wh...

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Published in:	European Journal of Nuclear Medicine and Molecular Imaging Vol. 48; no. 9; pp. 2846 - 2855
Main Authors:	Kubota, Manabu, Seki, Chie, Kimura, Yasuyuki, Takahata, Keisuke, Shimada, Hitoshi, Takado, Yuhei, Matsuoka, Kiwamu, Tagai, Kenji, Sano, Yasunori, Yamamoto, Yasuharu, Okada, Maki, Kikuchi, Tatsuya, Ichise, Masanori, Kawamura, Kazunori, Zhang, Ming-Rong, Higuchi, Makoto
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Science and Business Media LLC 01.08.2021 Springer Berlin Heidelberg Springer Nature B.V
Subjects:	Adenosine monophosphate Binding Blood C-MTP38 Cardiology Cerebellum Cyclic AMP Globus pallidus Imaging Ligands Medical imaging Medicine Medicine & Public Health Mental disorders Metabolites Neostriatum Neurology Nuclear Medicine Oncology Original Original Article Orthopedics PDE7 Phosphodiesterase Positron emission Positron emission tomography Quantification Radiology Sampling Thalamus Tomography Visualization PDE7 C-MTP38 Quantification Positron emission tomography
ISSN:	1619-7070, 1619-7089, 1619-7089
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Abstract	Purpose Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand 11 C-MTP38, which we recently developed, we aimed to image and quantify PDE7 in living human brains. Methods Seven healthy males underwent a 90-min PET scan after injection of 11 C-MTP38. We performed arterial blood sampling and metabolite analysis of plasma in six subjects to obtain a metabolite-corrected input function. Regional total distribution volumes ( V T s) were estimated using compartment models, and Logan plot and Ichise multilinear analysis (MA1). We further quantified the specific radioligand binding using the original multilinear reference tissue model (MRTM O ) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference. Results PET images with 11 C-MTP38 showed relatively high retentions in several brain regions, including in the striatum, globus pallidus, and thalamus, as well as fast washout from the cerebellar cortex, in agreement with the known distribution of PDE7. V T values were robustly estimated by two-tissue compartment model analysis (mean V T = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of 11 C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTM O and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTM O and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of 11 C-MTP38-PET. Conclusion We have provided the first demonstration of PET visualization of PDE7 in human brains. 11 C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7.
AbstractList	PurposePhosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand 11C-MTP38, which we recently developed, we aimed to image and quantify PDE7 in living human brains.MethodsSeven healthy males underwent a 90-min PET scan after injection of 11C-MTP38. We performed arterial blood sampling and metabolite analysis of plasma in six subjects to obtain a metabolite-corrected input function. Regional total distribution volumes (VTs) were estimated using compartment models, and Logan plot and Ichise multilinear analysis (MA1). We further quantified the specific radioligand binding using the original multilinear reference tissue model (MRTMO) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference.ResultsPET images with 11C-MTP38 showed relatively high retentions in several brain regions, including in the striatum, globus pallidus, and thalamus, as well as fast washout from the cerebellar cortex, in agreement with the known distribution of PDE7. VT values were robustly estimated by two-tissue compartment model analysis (mean VT = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of 11C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTMO and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTMO and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of 11C-MTP38-PET.ConclusionWe have provided the first demonstration of PET visualization of PDE7 in human brains. 11C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7. Purpose Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand 11 C-MTP38, which we recently developed, we aimed to image and quantify PDE7 in living human brains. Methods Seven healthy males underwent a 90-min PET scan after injection of 11 C-MTP38. We performed arterial blood sampling and metabolite analysis of plasma in six subjects to obtain a metabolite-corrected input function. Regional total distribution volumes ( V T s) were estimated using compartment models, and Logan plot and Ichise multilinear analysis (MA1). We further quantified the specific radioligand binding using the original multilinear reference tissue model (MRTM O ) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference. Results PET images with 11 C-MTP38 showed relatively high retentions in several brain regions, including in the striatum, globus pallidus, and thalamus, as well as fast washout from the cerebellar cortex, in agreement with the known distribution of PDE7. V T values were robustly estimated by two-tissue compartment model analysis (mean V T = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of 11 C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTM O and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTM O and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of 11 C-MTP38-PET. Conclusion We have provided the first demonstration of PET visualization of PDE7 in human brains. 11 C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7. Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand 11C-MTP38, which we recently developed, we aimed to image and quantify PDE7 in living human brains.PURPOSEPhosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric diseases. However, in vivo visualization of PDE7 in human brains has hitherto not been possible. Using the novel PET ligand 11C-MTP38, which we recently developed, we aimed to image and quantify PDE7 in living human brains.Seven healthy males underwent a 90-min PET scan after injection of 11C-MTP38. We performed arterial blood sampling and metabolite analysis of plasma in six subjects to obtain a metabolite-corrected input function. Regional total distribution volumes (VTs) were estimated using compartment models, and Logan plot and Ichise multilinear analysis (MA1). We further quantified the specific radioligand binding using the original multilinear reference tissue model (MRTMO) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference.METHODSSeven healthy males underwent a 90-min PET scan after injection of 11C-MTP38. We performed arterial blood sampling and metabolite analysis of plasma in six subjects to obtain a metabolite-corrected input function. Regional total distribution volumes (VTs) were estimated using compartment models, and Logan plot and Ichise multilinear analysis (MA1). We further quantified the specific radioligand binding using the original multilinear reference tissue model (MRTMO) and standardized uptake value ratio (SUVR) method with the cerebellar cortex as reference.PET images with 11C-MTP38 showed relatively high retentions in several brain regions, including in the striatum, globus pallidus, and thalamus, as well as fast washout from the cerebellar cortex, in agreement with the known distribution of PDE7. VT values were robustly estimated by two-tissue compartment model analysis (mean VT = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of 11C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTMO and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTMO and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of 11C-MTP38-PET.RESULTSPET images with 11C-MTP38 showed relatively high retentions in several brain regions, including in the striatum, globus pallidus, and thalamus, as well as fast washout from the cerebellar cortex, in agreement with the known distribution of PDE7. VT values were robustly estimated by two-tissue compartment model analysis (mean VT = 4.2 for the pallidum), Logan plot, and MA1, all in excellent agreement with each other, suggesting the reversibility of 11C-MTP38 binding. Furthermore, there were good agreements between binding values estimated by indirect method and those estimated by both MRTMO and SUVR, indicating that these methods could be useful for reliable quantification of PDE7. Because MRTMO and SUVR do not require arterial blood sampling, they are the most practical for the clinical use of 11C-MTP38-PET.We have provided the first demonstration of PET visualization of PDE7 in human brains. 11C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7.CONCLUSIONWe have provided the first demonstration of PET visualization of PDE7 in human brains. 11C-MTP38 is a promising novel PET ligand for the quantitative investigation of central PDE7.
Author	Kenji Tagai Yasuharu Yamamoto Maki Okada Makoto Higuchi Manabu Kubota Hitoshi Shimada Yasuyuki Kimura Kazunori Kawamura Masanori Ichise Keisuke Takahata Tatsuya Kikuchi Kiwamu Matsuoka Chie Seki Yasunori Sano Yuhei Takado Ming-Rong Zhang
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Snippet	Purpose Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in... PurposePhosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in... Phosphodiesterase 7 (PDE7) is an enzyme that selectively hydrolyses cyclic adenosine monophosphate, and its dysfunction is implicated in neuropsychiatric...
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SubjectTerms	Adenosine monophosphate Binding Blood C-MTP38 Cardiology Cerebellum Cyclic AMP Globus pallidus Imaging Ligands Medical imaging Medicine Medicine & Public Health Mental disorders Metabolites Neostriatum Neurology Nuclear Medicine Oncology Original Original Article Orthopedics PDE7 Phosphodiesterase Positron emission Positron emission tomography Quantification Radiology Sampling Thalamus Tomography Visualization
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Title	A first-in-human study of 11C-MTP38, a novel PET ligand for phosphodiesterase 7
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