[I-125] IODOPROXYFAN AND RELATED-COMPOUNDS - A REVERSIBLE RADIOLIGANDAND NOVEL CLASSES OF ANTAGONISTS WITH HIGH-AFFINITY AND SELECTIVITY FOR THE HISTAMINE HS RECEPTOR
H. Stark et al., [I-125] IODOPROXYFAN AND RELATED-COMPOUNDS - A REVERSIBLE RADIOLIGANDAND NOVEL CLASSES OF ANTAGONISTS WITH HIGH-AFFINITY AND SELECTIVITY FOR THE HISTAMINE HS RECEPTOR, Journal of medicinal chemistry, 39(6), 1996, pp. 1220-1226
The synthesis and biological evaluation of new histamine H-3 receptor
antagonists with an iodinated aryl partial structure are described as
part of an extensive research program to find model compounds for the
development of a new radioligand with high H-3 receptor affinity and s
pecific activity. All compounds were tested for their H-3 receptor ant
agonist activity in a [H-3]-histamine-release assay with synaptosomes
from rat cerebral cortex. The new leads with potent H-3 receptor antag
onist activity belong to a series of derivatives of 3-(1H-imidazol-4-y
l)propanol with carbamate (4-7), ester (8-16), and ether (17-22) as fu
nctional groups. Structure-activity relationships are discussed. The m
ost active compound in the functional test (-log K-i = 8.3) and in bin
ding studies with [H-3]-(R)-alpha-methylhistamine on rat cerebral cort
ex (-log K-i = 9.0) in vitro was 3-(1H-imidazol-4-yl)propyl(4-iodophen
l)methyl ether (iodoproxyfan, 19) exhibiting no central H-3 receptor a
ntagonist activity in vivo. The potency of iodopruxyfan is more than 3
00 times lower at H-1, H-2, alpha(1), alpha(2), beta(1), 5-HT2A, 5-HT3
, and M(3) receptors than at histamine H-3 receptors. Because of the h
igh potency and selectivity of 19, this compound has also been prepare
d in the [I-125]-iodinated form by a nucleophilic halogen exchange rea
ction using the corresponding bromo derivative 22 as a precursor. The
newly prepared [I-125]iodoproxyfan (23) possesses advantageous pharmac
ological properties and fulfills all criteria of a useful radioligand.