Abstract:
:Modifications to an N-methyl-(quinolin-4-yl)oxypropanamide scaffold were explored to discover leads for developing new radioligands for PET imaging of brain TSPO (translocator protein), a biomarker of neuroinflammation. Whereas contraction of the quinolinyl portion of the scaffold or cyclization of the tertiary amido group abolished high TSPO affinity, insertion of an extra nitrogen atom into the 2-arylquinolinyl portion was effective in retaining sub-nanomolar affinity for rat TSPO, while also decreasing lipophilicity to within the moderate range deemed preferable for a PET radioligand. Replacement of a phenyl group on the amido nitrogen with an isopropyl group was similarly effective. Among others, compound 20 (N-methyl-N-phenyl-2-[2-(pyridin-2-yl)-1,8-naphthyridin-4-yloxy]propanamide) appears especially appealing for PET radioligand development, based on high selectivity and high affinity (Ki = 0.5 nM) for rat TSPO, moderate lipophilicity (logD = 2.48), and demonstrated amenability to labeling with carbon-11.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Brouwer C,Jenko KJ,Zoghbi SS,Morse CL,Innis RB,Pike VWdoi
10.1016/j.ejmech.2016.08.046subject
Has Abstractpub_date
2016-11-29 00:00:00pages
677-688eissn
0223-5234issn
1768-3254pii
S0223-5234(16)30699-7journal_volume
124pub_type
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