Metal Protein-Attenuating Compound for PET Neuroimaging: Synthesis and Preclinical Evaluation of [11C]PBT2.

Dyshomeostasis or abnormal accumulation of metal ions such as copper, zinc, and iron have been linked to the pathogenesis of multiple neurodegenerative disorders including Alzheimer's disease (AD) and Huntington's disease (HD). 5,7-Dichloro-2-((dimethylamino)methyl)quinolin-8-ol, PBT2, is a second generation metal protein-attenuating compound that has recently advanced in Phase II clinical trials for the treatment of AD and HD based on promising preclinical efficacy data. Herein, we report the first radiosynthesis and preclinical positron emission tomography (PET) neuroimaging evaluation of [11C]PBT2 in rodents and nonhuman primates. Carbon-11 labeled PBT2 was synthesized in 4.8 ± 0.5% (nondecay corrected) radiochemical yield (RCY) at end-of-synthesis, based upon [11C]CH3I (n = 6), with >99% radiochemical purity and 80-90 GBq/μmol molar activity (Am) from the corresponding normethyl precursor. In the nonhuman primate brain, [11C]PBT2 uptake was extensive with peak concentration SUVpeak of 3.2-5.2 within 2.5-4.5 min postinjection in all cortical and subcortical gray matter regions (putamen > caudate > cortex ≫ white matter) followed by rapid washout from normal brain tissues. Furthermore, it is shown that [11C]PBT2 binds specifically in AD human brain tissue in vitro. The results presented here, combined with the clinical data available for PBT2, warrant the evaluation of [11C]PBT2 as an exploratory PET radiotracer in humans.

[1]  M. Nguyen,et al.  Structures of the Copper and Zinc Complexes of PBT2, a Chelating Agent Evaluated as Potential Drug for Neurodegenerative Diseases , 2017 .

[2]  M. Nguyen,et al.  Transfer of Copper from an Amyloid to a Natural Copper-Carrier Peptide with a Specific Mediating Ligand. , 2015, Chemistry.

[3]  Steven H. Liang,et al.  PET neuroimaging studies of [(18)F]CABS13 in a double transgenic mouse model of Alzheimer's disease and nonhuman primates. , 2015, ACS Chemical Neuroscience.

[4]  M. Sabbagh,et al.  Florbetaben for PET Imaging of Beta-Amyloid Plaques in the Brain , 2014, Neurology and Therapy.

[5]  Allen F. Brooks,et al.  Targeting Metal-Aβ Aggregates with Bifunctional Radioligand [11C]L2-b and a Fluorine-18 Analogue [18F]FL2-b , 2014, ACS medicinal chemistry letters.

[6]  George Jewell,et al.  Florbetapir F 18 amyloid PET and 36-month cognitive decline:a prospective multicenter study , 2014, Molecular Psychiatry.

[7]  Steven H. Liang,et al.  Rapid microfluidic flow hydrogenation for reduction or deprotection of 18F-labeled compounds. , 2013, Chemical communications.

[8]  A. Bush,et al.  Metallostasis in Alzheimer's disease. , 2013, Free radical biology & medicine.

[9]  Bing Zhou,et al.  Huntington disease arises from a combinatory toxicity of polyglutamine and copper binding , 2013, Proceedings of the National Academy of Sciences.

[10]  C. Kyriacou,et al.  Glutathione peroxidase activity is neuroprotective in models of Huntington's disease , 2013, Nature Genetics.

[11]  Ashley I. Bush,et al.  Metal dyshomeostasis and oxidative stress in Alzheimer’s disease , 2013, Neurochemistry International.

[12]  Alan A. Wilson,et al.  Synthesis and PET imaging studies of [18F]2-fluoroquinolin-8-ol ([18F]CABS13) in transgenic mouse models of Alzheimer's disease , 2012 .

[13]  P. Crouch,et al.  Therapeutic redistribution of metal ions to treat Alzheimer's disease. , 2012, Accounts of chemical research.

[14]  Andrei G. Vlassenko,et al.  PET amyloid-beta imaging in preclinical Alzheimer's disease. , 2012, Biochimica et biophysica acta.

[15]  C. Masters,et al.  Elevated labile Cu is associated with oxidative pathology in Alzheimer disease. , 2012, Free radical biology & medicine.

[16]  S. Bareggi,et al.  Clioquinol: Review of its Mechanisms of Action and Clinical Uses in Neurodegenerative Disorders , 2012, CNS neuroscience & therapeutics.

[17]  C. Masters,et al.  The Alzheimer’s therapeutic PBT2 promotes amyloid‐β degradation and GSK3 phosphorylation via a metal chaperone activity , 2011, Journal of neurochemistry.

[18]  Alison Abbott,et al.  Dementia: A problem for our age , 2011, Nature.

[19]  A. Bush,et al.  Metal Ionophore Treatment Restores Dendritic Spine Density and Synaptic Protein Levels in a Mouse Model of Alzheimer's Disease , 2011, PloS one.

[20]  R. Nanga,et al.  Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity , 2010, Proceedings of the National Academy of Sciences.

[21]  James Robert Brašić,et al.  In Vivo Imaging of Amyloid Deposition in Alzheimer Disease Using the Radioligand 18F-AV-45 (Flobetapir F 18) , 2010, Journal of Nuclear Medicine.

[22]  K. Blennow,et al.  PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses. , 2010, Journal of Alzheimer's disease : JAD.

[23]  F. Giorgini,et al.  Metallothioneins and copper metabolism are candidate therapeutic targets in Huntington's disease. , 2010, Biochemical Society transactions.

[24]  A. Rauk.  The chemistry of Alzheimer's disease. , 2009, Chemical Society reviews.

[25]  L. Thurfjell,et al.  Phase 1 Study of the Pittsburgh Compound B Derivative 18F-Flutemetamol in Healthy Volunteers and Patients with Probable Alzheimer Disease , 2009, Journal of Nuclear Medicine.

[26]  P. Faller,et al.  Bioinorganic Chemistry of Copper and Zinc Ions Coordinated to Amyloid‐β Peptide , 2009 .

[27]  H. Jacobsen,et al.  Alzheimer's disease: from pathology to therapeutic approaches. , 2009, Angewandte Chemie.

[28]  C. Jack,et al.  Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease , 2009, Brain : a journal of neurology.

[29]  William E. Klunk,et al.  The future of amyloid-beta imaging: a tale of radionuclides and tracer proliferation , 2008, Current opinion in neurology.

[30]  K. Blennow,et al.  Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial , 2008, The Lancet Neurology.

[31]  Ashley I. Bush,et al.  Therapeutics for Alzheimer’s disease based on the metal hypothesis , 2008, Neurotherapeutics.

[32]  S. Hersch,et al.  Mechanisms of Copper Ion Mediated Huntington's Disease Progression , 2007, PloS one.

[33]  H. Kozłowski,et al.  Copper homeostasis and neurodegenerative disorders (Alzheimer's, prion, and Parkinson's diseases and amyotrophic lateral sclerosis). , 2006, Chemical reviews.

[34]  C. Rowe,et al.  Radioiodinated clioquinol as a biomarker for β‐amyloid: Zn2+ complexes in Alzheimer's disease , 2006, Aging cell.

[35]  G. Hajak,et al.  Clioquinol treatment in familiar early onset of Alzheimer's disease: a case report. , 2005, Pharmacopsychiatry.

[36]  C. Rowe,et al.  The preparation of 123/125I‐clioquinol for the study of Aβ protein in Alzheimer's disease , 2005 .

[37]  C. Griesinger,et al.  Structural characterization of copper(II) binding to alpha-synuclein: Insights into the bioinorganic chemistry of Parkinson's disease. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[38]  W. Klunk,et al.  Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. , 2003, Journal of medicinal chemistry.

[39]  J. Valentine,et al.  Misfolded CuZnSOD and amyotrophic lateral sclerosis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[40]  C. Masters,et al.  Treatment with a Copper-Zinc Chelator Markedly and Rapidly Inhibits β-Amyloid Accumulation in Alzheimer's Disease Transgenic Mice , 2001, Neuron.

[41]  A. Bush,et al.  PBT2 Reduces Toxicity in a C. elegans Model of polyQ Aggregation and Extends Lifespan, Reduces Striatal Atrophy and Improves Motor Performance in the R6/2 Mouse Model of Huntington's Disease. , 2012, Journal of Huntington's disease.

[42]  A. Bush.  Drug development based on the metals hypothesis of Alzheimer's disease. , 2008, Journal of Alzheimer's disease : JAD.