Abstract Details

Title Evaluation of Phosphodiesterase 10A (PDE10A) Using MNI-659 PET Imaging in Huntington's Disease

Topic Movement Disorders

Presentation(s) P07 - (-)

Poster/Presentation
Number 212

Objective

Background BACKGROUND: In Huntington's disease (HD) degeneration of medium spiny neurons and striatal volume loss are prominent pathological findings. PDE10A is highly expressed in the striatal medium spiny neurons. Inhibition of PDE10A has been identified as a potential disease modifying mechanism for HD. Development of MNI-659, a PDE10A PET radiotracer, offers the potential both to investigate PDE10A expression in HD and to evaluate drug occupancy for PDE10A candidate therapeutics.

Design/Methods DESIGN/METHODS: Subjects with HD (n=5) and HV (n=5) were characterized clinically with standard HD scales and completed 18F-MNI-659 PET imaging. Subjects received 5 mCi (±0. 5) 18F-MNI-659 and serial dynamic PET projection data was acquired over 1.5 hrs. Binding potentials (BPnd) were measured for caudate, putamen, globus pallidus and striatum based on pharmacokinetic modeling using cerebellum as a reference region.

Results RESULTS: Mean age and gender for HD 63yrs (58-67) 4F:1M, and for HV 36yrs (29-46) 1F:4M. HD subjects had mild-moderate disease with means (range) on the following scales: total UHDRS 29.4 (18-46), UHDRS chorea score 8.8 (6-12), UHDRS behavioral score 7.5 (2-23), total functional capacity 11 (9-13), Independence Scale 92 (80-100) and MMSE 28.4 (27-30). 18F-MNI-659 mean BPnd for HD compared to HV by region: caudate HD 0.73, HV 2.13; putamen HD 1.41, HV 3.74; globus pallidus HD 1.60, HV 3.52; striatum HD 1.10, HV 2.93.

Conclusions CONCLUSIONS: In this pilot study, 18F-MNI-659 PET shows a markedly reduced binding (60-70%) in HD compared to HV with the most pronounced reduction in the caudate, consistent with expected pathological changes in HD. These data suggest a marked reduction in PDE10A expression in mild subjects. Ongoing studies will examine MNI-659 in pre-symptomatic HD to further explore the change in PDE10A expression in HD.

Authors/Disclosures
Danna L. Jennings, MD (Denali Therapeutics) PRESENTER	Dr. Jennings has received personal compensation for serving as an employee of Denali Therapeutics . Dr. Jennings has received stock or an ownership interest from Denali Therapeutics.
Jerzy P. Szaflarski, MD, PhD, FAAN (University of Alabama At Birmingham)	Dr. Szaflarski has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB Pharma. Dr. Szaflarski has received personal compensation in the range of $500-$4,999 for serving as a Consultant for LivaNova Inc. Dr. Szaflarski has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PureTech Health. Dr. Szaflarski has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Gidley, Sarli & Marusak, LLP. Dr. Szaflarski has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Szaflarski has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Law Firm. Dr. Szaflarski has stock in AdCel Biopharma, LLC. Dr. Szaflarski has stock in iFovea.
	No disclosure on file
Joseph H. Friedman, MD, FAAN (Butler Hospital)	No disclosure on file
David S. Russell, MD, PhD (Invicro)	Dr. Russell has received personal compensation for serving as an employee of Invicro. Dr. Russell has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Neurocrine. The institution of Dr. Russell has received research support from Biogen. The institution of Dr. Russell has received research support from Roche. The institution of Dr. Russell has received research support from Voyager. The institution of Dr. Russell has received research support from Eisai. The institution of Dr. Russell has received research support from Neuraly. The institution of Dr. Russell has received research support from Michael J. Fox Foundation. The institution of Dr. Russell has received research support from National Institutes for Health. The institution of Dr. Russell has received research support from Eli Lilly. The institution of Dr. Russell has received research support from Aprinoia.
	No disclosure on file
	No disclosure on file
John P. Seibyl, MD	Dr. Seibyl has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Invicro. Dr. Seibyl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Seibyl has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Life Molecular Imaging. Dr. Seibyl has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Dr. Seibyl has received stock or an ownership interest from Invicro.
Kenneth L. Marek, MD (IND)	Dr. Marek has received personal compensation for serving as an employee of IND. Dr. Marek has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for invicro. Dr. Marek has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Dr. Marek has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Marek has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biohaven. Dr. Marek has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for takeda. Dr. Marek has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Denali. Dr. Marek has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Koneksa. Dr. Marek has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Xingimaging. Dr. Marek has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuron23. Dr. Marek has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Dr. Marek has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biohaven. Dr. Marek has received research support from Michael J Fox Foundation.

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