their Sn congeners,6 and the only molecules released into
solution should be those of the labeled product. Moreover,
unlike arylstannanes, arylgermanes are robust toward a wide
range of conditions for chemical synthesis7 and so afford
the possibility to make a range of derivatives of an advanced
precursor prior to final radioiodinative release; a potentially
valuable feature during preclinical imaging agent develop-
ment. Herein, we describe proof-of-concept for this approach
as exemplified by the parallel, solid-phase synthesis (SPS)
of a small array of iodinated analogues of the CB1 receptor
inverse agonist rimonabant.
All reported rimonabant-derived radioiodinated ligands con-
tain the labeled iodine atom in place of the chlorine atom in
the C5 aryl ring; this substitution marginally reduces affinity
but increases selectivity for binding at CB1 vs CB2. Their
synthesis involves solution phase Pd(0)-mediated stannylation
of an arylbromide late intermediate (e.g., 5 f 6, Scheme 1)
Scheme 1
.
Standard Synthesis of a Radioiodinated Rimonabant
Analogue (e.g., AM281)
Type 1 cannabinoid (CB1) receptors belong to the rhodop-
sin family of G protein coupled receptors (GPCRs) and are
widely distributed in the central nervous system (CNS).8
Physiologically, they are implicated in regulation of pain,
energy distribution, and metabolism. Drug candidates acting
as antagonists/inverse agonists for these receptors have been/
are in clinical trials for treatment of obesity, metabolic
syndrome, and various addictions including smoking.9 Ri-
monabant (1a, marketed as acomplia) is a CB1 receptor
inverse agonist first approved for treatment of obesity by
the European Medicines Agency in 2006 and then withdrawn
from the market in 2008 following the emergence of
psychiatric disorders among patients.10 Various 11C-labeled,11
18F-labeled,12 and I123/124-labeled13 derivatives (e.g., 1b
[
123I]AM251 and 1c [123I]AM281, Figure 1) have proved to
then ipso-iododestannylation with a radiolabeled iodonium
source (e.g., 6 f 1c, Scheme 1).13
Experimental structure-activity relationship (SAR) data,
particularly in the context of previous attempts to develop
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Figure 1. Structures of rimonabant, AM251, and AM281.
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