TITLE:
Potential PET Ligands for Imaging of Cerebral VPAC and PAC Receptors: Are Non-Peptide Small Molecules Superior to Peptide Compounds?
AUTHORS:
Margit Pissarek
KEYWORDS:
Class B Receptors, Vasoactive Intestinal Peptide, Pituitary Adenylate Cyclase Activating Polypeptide, Non-Peptide Ligands, PET, SPECT
JOURNAL NAME:
World Journal of Neuroscience,
Vol.5 No.5,
November
17,
2015
ABSTRACT: Pituitary adenylate
cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP)
have been known for decades to mediate neuroendocrine and vasodilative actions
via G-protein-coupled receptors of Class B. These are targets of imaging probes
for positron emission tomography (PET) or single photon emission tomography
(SPECT) in tumor diagnostics and tumor grading. However, they play only a
subordinate role in the development of tracers for brain imaging. Difficulties
in development of non-peptide ligands typical for cerebral receptors of PACAP
and VIP are shared by all members of Class B receptor family. Essential
landmarks have been confirmed for understanding of structural details of Class
B receptor molecular signalling during the last five years. High relevance in
the explanation of problems in ligand development for these receptors is
admitted to the large N-terminalectodomain
markedly different from Class A receptor binding sites and poorly suitable as
orthosteric binding sites for the most small-molecule compounds. The present
study is focused on the recently available receptor ligands for PAC1, VPAC1 and
VPAC2 receptors as well as potential small-molecule lead structures suitable
for use in PET or SPECT. Recently, biaryl, cyanothiophene and pentanamide
structures with affinities in nM-range have been proposed as non-peptide
ligands at VPAC1 and VPAC2 receptors. However, most of these ligands have been
classified as non-competitive related to the orthosteric binding site of
endogenous peptide ligands of VPAC receptors. For PAC1 receptors have been
identified hydrazide compounds for which an inhibitory and potentially
competitive mechanism of receptor binding has been postulated based on
molecular docking studies.