Radiosynthesis and preclinical evaluation of [11C]Cimbi‐701 – Towards the imaging of cerebral 5‐HT7 receptors

Radiosynthesis and preclinical evaluation of [11C]Cimbi‐701 – Towards the imaging of cerebral... The serotonin 7 (5‐HT7) receptor is suggested to be involved in a broad variety of CNS disorders, but very few in vivo tools exist to study this important target. Molecular imaging with positron emission tomography (PET) would enable an in vivo characterization of the 5‐HT7 receptor. However, no clinical PET radiotracer exists for this receptor, and thus we aimed to develop such a tracer. In this study, we present the preclinical evaluation of [11C]Cimbi‐701. Cimbi‐701 was synthesized in a one‐step procedure starting from SB‐269970. Its selectivity profile was determined using an academic screening platform (NIMH Psychoactive Drug Screening Program). Successful radiolabeling of [11C]Cimbi‐701 and subsequent in vivo evaluation was conducted in rats, pigs and baboon. In vivo specificity was investigated by 5‐HT7 and σ receptor blocking studies. P‐gp efflux transporter dependency was investigated using elacridar. [11C]Cimbi‐701 could successfully be synthesized. Selectivity profiling revealed high affinity for the 5‐HT7 (Ki = 18 nM), σ‐1 (Ki = 9.2 nM) and σ‐2 (Ki = 1.6 nM) receptors. In rats, [11C]Cimbi‐701 acted as a strong P‐gp substrate. After P‐gp inhibition, rat brain uptake could specifically be blocked by 5‐HT7 and σ receptor ligands. In pig, high brain uptake and specific 5‐HT7 and σ‐receptor binding was found for [11C]Cimbi‐701 without P‐gp inhibition. Finally, low brain uptake was found in baboons. Both the specific σ‐receptor binding and the low brain uptake of [11C]Cimbi‐701 displayed in baboon discouraged further translation to humans. Instead, we suggest exploration of this structural class as results indicate that selective 5‐HT7 receptor imaging might be possible when more selective non‐P‐gp substrates are identified. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Labelled Compounds and Radiopharmaceuticals Wiley

Loading next page...
 
/lp/wiley/radiosynthesis-and-preclinical-evaluation-of-11c-cimbi-701-towards-the-B7RP0GLrZr
Publisher
Wiley
Copyright
© 2020 John Wiley & Sons, Ltd.
ISSN
0362-4803
eISSN
1099-1344
DOI
10.1002/jlcr.3808
Publisher site
See Article on Publisher Site

Abstract

The serotonin 7 (5‐HT7) receptor is suggested to be involved in a broad variety of CNS disorders, but very few in vivo tools exist to study this important target. Molecular imaging with positron emission tomography (PET) would enable an in vivo characterization of the 5‐HT7 receptor. However, no clinical PET radiotracer exists for this receptor, and thus we aimed to develop such a tracer. In this study, we present the preclinical evaluation of [11C]Cimbi‐701. Cimbi‐701 was synthesized in a one‐step procedure starting from SB‐269970. Its selectivity profile was determined using an academic screening platform (NIMH Psychoactive Drug Screening Program). Successful radiolabeling of [11C]Cimbi‐701 and subsequent in vivo evaluation was conducted in rats, pigs and baboon. In vivo specificity was investigated by 5‐HT7 and σ receptor blocking studies. P‐gp efflux transporter dependency was investigated using elacridar. [11C]Cimbi‐701 could successfully be synthesized. Selectivity profiling revealed high affinity for the 5‐HT7 (Ki = 18 nM), σ‐1 (Ki = 9.2 nM) and σ‐2 (Ki = 1.6 nM) receptors. In rats, [11C]Cimbi‐701 acted as a strong P‐gp substrate. After P‐gp inhibition, rat brain uptake could specifically be blocked by 5‐HT7 and σ receptor ligands. In pig, high brain uptake and specific 5‐HT7 and σ‐receptor binding was found for [11C]Cimbi‐701 without P‐gp inhibition. Finally, low brain uptake was found in baboons. Both the specific σ‐receptor binding and the low brain uptake of [11C]Cimbi‐701 displayed in baboon discouraged further translation to humans. Instead, we suggest exploration of this structural class as results indicate that selective 5‐HT7 receptor imaging might be possible when more selective non‐P‐gp substrates are identified.

Journal

Journal of Labelled Compounds and RadiopharmaceuticalsWiley

Published: Feb 1, 2020

Keywords: ; ; ;

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create folders to
organize your research

Export folders, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off