• Skip to primary navigation
  • Skip to main content
SRI logo
  • About
    • Press room
    • Our history
  • Expertise
    • Advanced imaging systems
    • Artificial intelligence
    • Biomedical R&D services
    • Biomedical sciences
    • Computer vision
    • Cyber & formal methods
    • Education and learning
    • Innovation strategy and policy
    • National security
    • Ocean & space
    • Quantum
    • Robotics, sensors & devices
    • Speech & natural language
    • Video test & measurement
  • Ventures
  • NSIC
  • Careers
  • Contact
  • 日本支社
Search
Close
Biomedical sciences publications May 1, 2015

Pharmacological Characterization of RO5461861, a Potent and Selective PDE10A Inhibitor

Citation

Copy to clipboard


Schaffhauser, H., Prinssen, E. P., Honer, M., Ballard, T. M., Wallace, T. L., Peters, J.-U., . . . Flohr, A. (2014, 15-19 November). Pharmacological characterization of RO5461861, a potent and selective PDE10A inhibitor. Paper presented at Neuroscience 2014, Washington, DC.

Abstract

Inhibition of PDE10A is considered a promising approach for the treatment of multiple symptomatic domains of schizophrenia and Huntington’s Disease (HD). Here we describe the characterization of a new class of potent PDE10A inhibitors exemplified by 4-(Azetidine-1 -carbonyl)-2-methyl-2-H-pyrazole-3-carboxylic acid (2-phenylimidazo[1,2-a]pyrimidin-7-yl)-amide (RO5461861) in vitro as well as in behavioral tests relevant to NMDA-R hypofunction and working memory. RO5461861 inhibited the PDE10A enzyme with nanomolar potency, was selective against the other members of the phosphodiesterase family and had good pharmacokinetic properties in different preclinical species. The binding of [3H]RO5461861 was characterized in both rat striatal membranes as well as in brain sections. Blocking and displacement experiments were performed using reported selective PDE10A inhibitors. [3H]RO5461861 binding was saturable in the rat striatum and demonstrated high-affinity binding to a single site. The calculated Kd and Bmax values were 1.35 ± 0.35 nM and 3.99 ± 0.26 pmol mg-1 of protein respectively. In sagittal sections of rat brain, a high density of specific binding was observed in the striatum, substantia nigra, olfactory tubercle and globus pallidus. Less binding was observed in the hippocampus, in the different layers of the cortex and cerebellum. Oral administration of RO5461861 dose dependently reversed ketamine-induced hyperlocomotion in mice and MK801-induced hyperlocomotion in rats with ED50s of 0.7 and 0.87 mg/kg respectively. Catalepsy in rats was observed only at higher doses (minimally effective dose [MED] = 3 mg/kg). RO5461861 increased accuracy in the delayed match to sample (DMTS) in Cynomolgus macaques at a dose (3 mg/kg, oral) which did not produce extrapyramidal symptoms. Collectively, the present data demonstrate that RO5461861 has utility in investigating the potential of PDE10A inhibition for the treatment of schizophrenia or HD and highlight the value of [3H]RO5461861 in characterizing new chemical entities.

↓ View online

Share this
Career call to action image

Work with us

Search jobs

How can we help?

Once you hit send…

We’ll match your inquiry to the person who can best help you.

Expect a response within 48 hours.

Our work

Case studies

Publications

Timeline of innovation

Areas of expertise

Institute

Leadership

Press room

Media inquiries

Compliance

Careers

Job listings

Contact

SRI Ventures

Our locations

Headquarters

333 Ravenswood Ave
Menlo Park, CA 94025 USA

+1 (650) 859-2000

Subscribe to our newsletter


日本支社
SRI International
  • Contact us
  • Privacy Policy
  • Cookies
  • DMCA
  • Copyright © 2023 SRI International
Manage Cookie Consent
To provide the best experiences, we use technologies like cookies to store and/or access device information. Consenting to these technologies will allow us to process data such as browsing behavior or unique IDs on this site. Not consenting or withdrawing consent, may adversely affect certain features and functions.
Functional Always active
The technical storage or access is strictly necessary for the legitimate purpose of enabling the use of a specific service explicitly requested by the subscriber or user, or for the sole purpose of carrying out the transmission of a communication over an electronic communications network.
Preferences
The technical storage or access is necessary for the legitimate purpose of storing preferences that are not requested by the subscriber or user.
Statistics
The technical storage or access that is used exclusively for statistical purposes. The technical storage or access that is used exclusively for anonymous statistical purposes. Without a subpoena, voluntary compliance on the part of your Internet Service Provider, or additional records from a third party, information stored or retrieved for this purpose alone cannot usually be used to identify you.
Marketing
The technical storage or access is required to create user profiles to send advertising, or to track the user on a website or across several websites for similar marketing purposes.
Manage options Manage services Manage {vendor_count} vendors Read more about these purposes
View preferences
{title} {title} {title}