OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disease characterized by aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) in the brain. The aim of this study was to develop and evaluate the effectiveness of a novel radioiodinated tracer, 6-[125 I]iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)isoquinoline ([125 I]IPPI), for binding to Tau protein (Ki = 0.75 nM) in postmortem human brain (AD and cognitively normal (CN). METHODS: Radiosynthesis of [125 I]IPPI was carried out by radioiododestannylation and purified chromatographically. Computational modeling studies of IPPI and MK-6240 binding on Tau fibril were evaluated. In vitro autoradiography studies were carried out with [3 H]PIB for Aβ plaques and [125 I]IPPI for Tau in AD and CN brains and evaluate drug effects. RESULTS: [125 I]IPPI was produced in >95% purity. Molecular modeling of IPPI revealed binding energies of IPPI (-7.8, -8.1, -8.2, -7.5 Kcal/mol) at the four sites were comparable to MK-6240 (-8.7, -8.5, -8.3, -7.5 Kcal/mol). Ratio of average grey matter (GM) [125 I]IPPI in AD versus CN was found to be 7.31 (p = .07) and AD GM/ white matter (WM) = 4.35 (p = .09). Ratio of average GM/WM [125 I]IPPI in CN was 1.21. Binding of [125 I]IPPI correlated with the presence of Tau, confirmed by anti-Tau Dako A0024. Specifically bound [125 I]IPPI to Tau in AD brains was displaced by MK-6240 and IPPI (>90%). Monoamine oxidase inhibitors (MAO) inhibitors deprenyl and clorgyline effected [125 I]IPPI binding at >1 µM concentrations. CONCLUSION: [125 I]IPPI exhibited high binding in human AD frontal cortex and anterior cingulate and is a suitable radioiodinated ligand for Tau imaging.
OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disease characterized by aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) in the brain. The aim of this study was to develop and evaluate the effectiveness of a novel radioiodinated tracer, 6-[125 I]iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)isoquinoline ([125 I]IPPI), for binding to Tau protein (Ki = 0.75 nM) in postmortem human brain (AD and cognitively normal (CN). METHODS: Radiosynthesis of [125 I]IPPI was carried out by radioiododestannylation and purified chromatographically. Computational modeling studies of IPPI and MK-6240 binding on Tau fibril were evaluated. In vitro autoradiography studies were carried out with [3 H]PIB for Aβ plaques and [125 I]IPPI for Tau in AD and CN brains and evaluate drug effects. RESULTS: [125 I]IPPI was produced in >95% purity. Molecular modeling of IPPI revealed binding energies of IPPI (-7.8, -8.1, -8.2, -7.5 Kcal/mol) at the four sites were comparable to MK-6240 (-8.7, -8.5, -8.3, -7.5 Kcal/mol). Ratio of average grey matter (GM) [125 I]IPPI in AD versus CN was found to be 7.31 (p = .07) and AD GM/ white matter (WM) = 4.35 (p = .09). Ratio of average GM/WM [125 I]IPPI in CN was 1.21. Binding of [125 I]IPPI correlated with the presence of Tau, confirmed by anti-Tau Dako A0024. Specifically bound [125 I]IPPI to Tau in AD brains was displaced by MK-6240 and IPPI (>90%). Monoamine oxidase inhibitors (MAO) inhibitors deprenyl and clorgyline effected [125 I]IPPI binding at >1 µM concentrations. CONCLUSION: [125 I]IPPI exhibited high binding in human AD frontal cortex and anterior cingulate and is a suitable radioiodinated ligand for Tau imaging.
Authors: Lindsey R Drake; Jonathan M Pham; Timothy J Desmond; Andrew V Mossine; So Jeong Lee; Michael R Kilbourn; Robert A Koeppe; Allen F Brooks; Peter J H Scott Journal: ACS Chem Neurosci Date: 2019-08-05 Impact factor: 4.418
Authors: Thomas G Beach; Charles H Adler; Lucia I Sue; Geidy Serrano; Holly A Shill; Douglas G Walker; LihFen Lue; Alex E Roher; Brittany N Dugger; Chera Maarouf; Alex C Birdsill; Anthony Intorcia; Megan Saxon-Labelle; Joel Pullen; Alexander Scroggins; Jessica Filon; Sarah Scott; Brittany Hoffman; Angelica Garcia; John N Caviness; Joseph G Hentz; Erika Driver-Dunckley; Sandra A Jacobson; Kathryn J Davis; Christine M Belden; Kathy E Long; Michael Malek-Ahmadi; Jessica J Powell; Lisa D Gale; Lisa R Nicholson; Richard J Caselli; Bryan K Woodruff; Steven Z Rapscak; Geoffrey L Ahern; Jiong Shi; Anna D Burke; Eric M Reiman; Marwan N Sabbagh Journal: Neuropathology Date: 2015-01-26 Impact factor: 1.906
Authors: Cinthya Aguero; Maeva Dhaynaut; Marc D Normandin; Ana C Amaral; Nicolas J Guehl; Ramesh Neelamegam; Marta Marquie; Keith A Johnson; Georges El Fakhri; Matthew P Frosch; Teresa Gomez-Isla Journal: Acta Neuropathol Commun Date: 2019-03-11 Impact factor: 7.801
Authors: Anthony W P Fitzpatrick; Benjamin Falcon; Shaoda He; Alexey G Murzin; Garib Murshudov; Holly J Garringer; R Anthony Crowther; Bernardino Ghetti; Michel Goedert; Sjors H W Scheres Journal: Nature Date: 2017-07-05 Impact factor: 49.962