Bennacef et al.
SCHEME 1. NK-3 Receptor Antagonists 1 and 2 and
be rapid, efficient, selective, and preferably without any
intermediate purification. Moreover, carbon-11 is available from
the cyclotron only in forms of [11C]CO2 and [11C]CH4 then
giving access to a limited number of labeled precursors (e.g.,
[11C]HCN, [11C]CO, [11C]COCl2, [11C]CH3I). The radiolabeling
strategy based on the Stille reaction was attractive for several
reasons: (i) the pallado-catalyzed cross-coupling reaction usually
proceeds under conditions compatible with a broad range of
functional groups;9 (ii) it used [11C]-methyl iodide as radiola-
beled precursor synthetically well-established in all PET centers;
(iii) it has been previously proved to be compatible with carbon-
11 chemistry and used successfully for the synthesis of several
PET radiotracers;10,11 and (iv) the resulting Csp2-11Csp3 bond
would be stable in vivo. Due to the high reactivity of the
trimethylstannyl derivatives compared to that of the tributyl-
stannyl analogues, we undertook to work with the tin precursor
3, although a competitive transfer of an unlabeled group leading
to a reduced specific radioactivity could not be excluded.10c
The synthesis of quinoline 3 was not straightforward due to
the limited reported methods giving direct access to 2-phe-
nylquinoline-4-carboxylic derivatives functionalized at the posi-
tion 3. Quinoline-4-carboxylic acids bearing a phenyl group at
position 2 were usually prepared by Pfitzinger4b,e,12 or Doebner13
reactions. Recently, we developed a one-step synthesis of
2-phenylquinoline-4-carboxylates and carboxamides from
arylimines and acrylates or acrylamides.14 This former, as well
as the Doebner reaction corresponding to a three-component
reaction between pyruvic acid, benzaldehyde, and an aniline,
was restricted to 3-unsubstituted heterocycles. The Pfitzinger
reaction involving an isatin and an aryl methyl ketone in the
Strategy to Label 2 with Carbon-11 (*C ) 12C or 11C)
Talnetant 1, hNK-3-CHO binding Ki ) 1.0 nM), represent a
class of highly potent antagonists of the NK-3 receptor.4 Clinical
trials revealed that Talnetant 1 had an antipsychotic efficacy
with an excellent tolerability and a beneficial impact on
cognitive deficit in schizophrenia.5 With the aim of developing
radioligands for PET and SPECT studies, we previously
synthesized fluorinated and iodinated quinolinecarboxamides
that retained the affinity of Talnetant.6 The labeling with
fluorine-187 (â+ emitter, t1/2 ) 109.7 min) or iodine-1238 (γ
emitter, t1/2 ) 13.2 h) of these compounds is now underway
for evaluation as NK-3 radioligands.
In the 2-phenylquinoline-4-carboxamide series, SB 222200
2 had also to be considered as a ligand suitable for a
radiolabeling (Scheme 1). Indeed, its pharmacological profile
demonstrated high affinity (slightly lower than that of Talnetant
1, hNK-3-CHO binding Ki ) 4.2 nM), selectivity toward the
other subtypes (Ki hNK-1/Ki hNK-3 > 105; Ki hNK-2/Ki hNK-3
> 250), reversible binding, and central nervous system penetra-
tion (Talnetant being only moderately CNS penetrant).4b,e-g
From a radiochemical point of view, the presence of a methyl
group onto the quinoline ring allowed us to envisage a labeling
with carbon-11 (â+ emitter, t1/2 ) 20.4 min) using a Stille
coupling reaction (Scheme 1).
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radioactivity, the short half-life of the radioisotope, and the use
of sub-micromolar quantities of the labeled reactant. The
synthesis time is a crucial parameter, and the reactions have to
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