cn0c00074_si_001.pdf (1.54 MB)
Translation of HDAC6 PET Imaging Using [18F]EKZ-001–cGMP Production and Measurement of HDAC6 Target Occupancy in Nonhuman Primates
Version 2 2021-09-24, 19:43
Version 1 2020-03-19, 15:41
journal contribution
posted on 2021-09-24, 19:43 authored by Sofie Celen, Johanna Rokka, Tonya M. Gilbert, Michel Koole, Isabeau Vermeulen, Kim Serdons, Frederick A. Schroeder, Florence F. Wagner, Tom Bleeser, Baileigh G. Hightower, Jiyun Hu, Dania Rahal, Hudson Beyzavi, Wim Vanduffel, Koen Van Laere, Janice E. Kranz, Jacob M. Hooker, Guy Bormans, Christopher J. CawthorneHistone deacetylase 6 (HDAC6) is a multifunctional cytoplasmic
enzyme involved in diverse cellular processes such as intracellular
transport and protein quality control. Inhibition of HDAC6 can alleviate
defects in cell and rodent models of certain diseases, particularly
neurodegenerative disorders, including Alzheimer’s disease
and amyotrophic lateral sclerosis. However, while HDAC6 represents
a potentially powerful therapeutic target, development of effective
brain-penetrant HDAC6 inhibitors remains challenging. Recently, [18F]EKZ-001 ([18F]Bavarostat), a brain-penetrant
positron emission tomography (PET) radioligand with high affinity
and selectivity toward HDAC6, was developed and evaluated preclinically
for its ability to bind HDAC6. Herein, we describe the efficient and
robust fully automated current Good Manufacturing Practices (cGMP)
compliant production method. [18F]EKZ-001 quantification
methods were validated in nonhuman primates (NHP) using full kinetic
modeling, and [18F]EKZ-001 PET was applied to compare dose-occupancy
relationships between two HDAC6 inhibitors, EKZ-317 and ACY-775. [18F]EKZ-001 is cGMP produced with an average decay-corrected
radiochemical yield of 14% and an average molar activity of 204 GBq/μmol.
We demonstrate that a two-tissue compartmental model and Logan graphical
analysis are appropriate for [18F]EKZ-001 PET quantification
in NHP brain. Blocking studies show that the novel compound EKZ-317
achieves higher target occupancy than ACY-775. This work supports
the translation of [18F]EKZ-001 PET for first-in-human
studies.
History
Usage metrics
Categories
Keywords
tissue compartmental modelprotein quality controlparticularly neurodegenerative disorderslogan graphical analysisincluding alzheimer ’diverse cellular processescorrected radiochemical yieldcompliant production methodamyotrophic lateral sclerosis18 supblocking studies showaverage molar activity001 quantification methodsselectivity toward hdac6novel compound ekz001 ([< suphdac6 target occupancy001 pet quantificationtwo hdac6 inhibitorsf ] ekz[< supoccupancy relationshipshuman studiesaverage decay001 pethdac6 representsbind hdac6work supportsrodent modelsnonhuman primatesintracellular transporthigh affinityevaluated preclinicallycompare dosecertain diseasesalleviate defects204 gbq
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC