[11C]CUMI-101, a positron emission tomographic radioligand, behaves as a serotonin 1A receptor antagonist and also binds to alpha1A receptors in brain

Thursday, November 07, 2013 — Poster Session II
12:00 p.m. – 2:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NIMH	PHARM-9

Authors

S Shrestha
JS Liow
S Lu
K Jenko
R Gladding
P Svenningsson
C Morse
S Zoghbi
V Pike
R Innis

Abstract

The positron emission tomographic (PET) radioligand [11C]CUMI-101 was previously suggested as a putative agonist radioligand for the 5-HT1A receptor in rat brain. However, a recent study showed that CUMI-101 behaved as a potent 5-HT1A receptor antagonist. CUMI-101 also has moderate affinity (KD = 6.75 nM) for alpha1A (α1A) receptors measured in vitro. The current study examined the functional properties and selectivity of CUMI-101, both in vitro and in vivo. The functional assay was performed using [35S]GTPγS in primate brains. CUMI-101’s cross-reactivity with α1A receptors was performed using in vitro radioligand binding studies in rat, monkey, and human brain, as well as in vivo PET imaging. CUMI-101 behaved as a potent 5-HT1A receptor antagonist by dose-dependently inhibiting 8-OH-DPAT-stimulated [35S]GTPγS binding. Both in vitro and in vivo studies showed that CUMI-101 had significant α1A receptor cross-reactivity. On average, across all three species examined, cross-reactivity was highest in thalamus (>45%), and lowest in neocortex and cerebellum (<10%). Taken together, the results suggest that CUMI-101 is a potent 5-HT1A receptor antagonist with significant, regional-dependent cross-reactivity with the α1A receptor. Thus, potential use of [11C]CUMI-101 as a PET radioligand in humans is limited.