Aline Delva1,2, Michel Koole3, Wim Vandenberghe1,2, Koen Van Laere4,5, Kim Serdons6, Guy Bormans7, Longbin Liu8, Jonathan Bard8, Vinod Khetarpal8, Celia Dominguez8, Ignacio Munoz-Sanjuan8, Andrew Wood8, Mette Skinbjerg8, Yuchuan Wang8. 1. Department of Neurosciences, KU Leuven, Leuven, Belgium. 2. Department of Neurology, University Hospitals Leuven, Leuven, Belgium. 3. Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium. 4. Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium. koen.vanlaere@uzleuven.be. 5. Division of Nuclear Medicine, University Hospitals Leuven, Leuven, België. koen.vanlaere@uzleuven.be. 6. Department of Radiopharmacy, University Hospitals Leuven, Leuven, Belgium. 7. Lab Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. 8. CHDI Management/CHDI Foundation, Princeton, NJ, 08540, USA.
Abstract
PURPOSE: Huntington's disease is caused by a trinucleotide expansion in the HTT gene, which leads to aggregation of mutant huntingtin (mHTT) protein in the brain and neurotoxicity. Direct in vivo measurement of mHTT aggregates in human brain parenchyma is not yet possible. In this first-in-human study, we investigated biodistribution and dosimetry in healthy volunteers of [11C]CHDI-00485180-R ([11C]CHDI-180R) and [11C]CHDI-00485626 ([11C]CHDI-626), two tracers designed for PET imaging of aggregated mHTT in the brain that have been validated in preclinical models. METHODS: Biodistribution and radiation dosimetry studies were performed in 3 healthy volunteers (age 25.7 ± 0.5 years; 2 F) for [11C]CHDI-180R and in 3 healthy volunteers (age 35.3 ± 6.8 years; 2 F) for [11C]CHDI-626 using sequential whole-body PET-CT. Source organs were delineated in 3D using combined PET and CT data. Individual organ doses and effective doses were determined using OLINDA 2.1. RESULTS: There were no clinically relevant adverse events. The mean effective dose (ED) for [11C]CHDI-180R was 4.58 ± 0.65 μSv/MBq, with highest absorbed doses for liver (16.9 μGy/MBq), heart wall (15.9 μGy/MBq) and small intestine (15.8 μGy/MBq). Mean ED for [11C]CHDI-626 was 5.09 ± 0.06 μSv/MBq with the highest absorbed doses for the gallbladder (26.5 μGy/MBq), small intestine (20.4 μGy/MBq) and liver (19.6 μGy/MBq). Decay-corrected brain uptake curves showed promising kinetics for [11C]CHDI-180R, but for [11C]CHDI-626 an increasing signal over time was found, probably due to accumulation of a brain-penetrant metabolite. CONCLUSION: [11C]CHDI-180R and [11C]CHDI-626 are safe for in vivo PET imaging in humans. The estimated radiation burden is in line with most 11C-ligands. While [11C]CHDI-180R has promising kinetic properties in the brain, [11C]CHDI-626 is not suitable for human in vivo mHTT PET due to the possibility of a radiometabolite accumulating in brain parenchyma. TRIAL REGISTRATION: EudraCT number 2020-002129-27. CLINICALTRIALS: gov NCT05224115 (retrospectively registered).
PURPOSE: Huntington's disease is caused by a trinucleotide expansion in the HTT gene, which leads to aggregation of mutant huntingtin (mHTT) protein in the brain and neurotoxicity. Direct in vivo measurement of mHTT aggregates in human brain parenchyma is not yet possible. In this first-in-human study, we investigated biodistribution and dosimetry in healthy volunteers of [11C]CHDI-00485180-R ([11C]CHDI-180R) and [11C]CHDI-00485626 ([11C]CHDI-626), two tracers designed for PET imaging of aggregated mHTT in the brain that have been validated in preclinical models. METHODS: Biodistribution and radiation dosimetry studies were performed in 3 healthy volunteers (age 25.7 ± 0.5 years; 2 F) for [11C]CHDI-180R and in 3 healthy volunteers (age 35.3 ± 6.8 years; 2 F) for [11C]CHDI-626 using sequential whole-body PET-CT. Source organs were delineated in 3D using combined PET and CT data. Individual organ doses and effective doses were determined using OLINDA 2.1. RESULTS: There were no clinically relevant adverse events. The mean effective dose (ED) for [11C]CHDI-180R was 4.58 ± 0.65 μSv/MBq, with highest absorbed doses for liver (16.9 μGy/MBq), heart wall (15.9 μGy/MBq) and small intestine (15.8 μGy/MBq). Mean ED for [11C]CHDI-626 was 5.09 ± 0.06 μSv/MBq with the highest absorbed doses for the gallbladder (26.5 μGy/MBq), small intestine (20.4 μGy/MBq) and liver (19.6 μGy/MBq). Decay-corrected brain uptake curves showed promising kinetics for [11C]CHDI-180R, but for [11C]CHDI-626 an increasing signal over time was found, probably due to accumulation of a brain-penetrant metabolite. CONCLUSION: [11C]CHDI-180R and [11C]CHDI-626 are safe for in vivo PET imaging in humans. The estimated radiation burden is in line with most 11C-ligands. While [11C]CHDI-180R has promising kinetic properties in the brain, [11C]CHDI-626 is not suitable for human in vivo mHTT PET due to the possibility of a radiometabolite accumulating in brain parenchyma. TRIAL REGISTRATION: EudraCT number 2020-002129-27. CLINICALTRIALS: gov NCT05224115 (retrospectively registered).
Authors: Edward J Wild; Roberto Boggio; Douglas Langbehn; Nicola Robertson; Salman Haider; James R C Miller; Henrik Zetterberg; Blair R Leavitt; Rainer Kuhn; Sarah J Tabrizi; Douglas Macdonald; Andreas Weiss Journal: J Clin Invest Date: 2015-04-06 Impact factor: 14.808
Authors: Longbin Liu; Michael E Prime; Matt R Lee; Vinod Khetarpal; Christopher J Brown; Peter D Johnson; Patricia Miranda-Azpiazu; Xuemei Chen; Daniel Clark-Frew; Samuel Coe; Randall Davis; Anthony Dickie; Andreas Ebneth; Simone Esposito; Elise Gadouleau; Xinjie Gai; Sebastien Galan; Samantha Green; Catherine Greenaway; Paul Giles; Christer Halldin; Sarah Hayes; Todd Herbst; Frank Herrmann; Manuela Heßmann; Zhisheng Jia; Alexander Kiselyov; Adrian Kotey; Thomas Krulle; John E Mangette; Richard W Marston; Sergio Menta; Matthew R Mills; Edith Monteagudo; Sangram Nag; Martina Nibbio; Laura Orsatti; Sabine Schaertl; Christoph Scheich; Joanne Sproston; Vladimir Stepanov; Marie Svedberg; Akihiro Takano; Malcolm Taylor; Wayne Thomas; Miklós Toth; Darshan Vaidya; Katarina Vanräs; Derek Weddell; Ian Wigginton; John Wityak; Ladislav Mrzljak; Ignacio Munoz-Sanjuan; Jonathan A Bard; Celia Dominguez Journal: J Med Chem Date: 2020-07-30 Impact factor: 7.446
Authors: Longbin Liu; Peter D Johnson; Michael E Prime; Vinod Khetarpal; Matthew R Lee; Christopher J Brown; Xuemei Chen; Daniel Clark-Frew; Samuel Coe; Mike Conlon; Randall Davis; Samantha Ensor; Simone Esposito; Anton Forsberg Moren; Xinjie Gai; Samantha Green; Catherine Greenaway; James Haber; Christer Halldin; Sarah Hayes; Todd Herbst; Frank Herrmann; Manuela Heßmann; Ming Min Hsai; Adrian Kotey; John E Mangette; Matthew R Mills; Edith Monteagudo; Sangram Nag; Martina Nibbio; Laura Orsatti; Sabine Schaertl; Christoph Scheich; Joanne Sproston; Vladimir Stepanov; Katarina Varnäs; Andrea Varrone; John Wityak; Ladislav Mrzljak; Ignacio Munoz-Sanjuan; Jonathan A Bard; Celia Dominguez Journal: J Med Chem Date: 2021-08-05 Impact factor: 7.446
Authors: Joaquim J Ferreira; Filipe B Rodrigues; Gonçalo S Duarte; Tiago A Mestre; Anne-Catherine Bachoud-Levi; Anna Rita Bentivoglio; Jean-Marc Burgunder; Francisco Cardoso; Daniel O Claassen; G Bernard Landwehrmeyer; Jaime Kulisevsky; Melissa J Nirenberg; Anne Rosser; Jan Roth; Klaus Seppi; Jaroslaw Slawek; Erin Furr-Stimming; Sarah J Tabrizi; Francis O Walker; Wim Vandenberghe; João Costa; Cristina Sampaio Journal: Mov Disord Date: 2021-11-29 Impact factor: 9.698
Authors: Gillian P Bates; Ray Dorsey; James F Gusella; Michael R Hayden; Chris Kay; Blair R Leavitt; Martha Nance; Christopher A Ross; Rachael I Scahill; Ronald Wetzel; Edward J Wild; Sarah J Tabrizi Journal: Nat Rev Dis Primers Date: 2015-04-23 Impact factor: 52.329