Pd catalyzed cross-coupling of [11C]MeLi and its application in the synthesis and evaluation of a potential PET tracer for the vesicular acetylcholine transporter (VAChT)

Introduction
The short half-life of 11C (t1/2 = 20.33 min) requires ultra-fast reactivity in order to perform efficient labelling of PET tracers. A recently discovered cross-coupling methodology1 enables the coupling between aryl bromides and organolithium reagents within seconds and therefore can be an attractive strategy to access 11C-labelled compounds. In this work several clinically relevant structures were labelled via this method. The scope of the reaction was further explored and expanded, allowing radiolabelling of highly reactive compounds, such as aldehydes. Then we focused our attention on the development of a new potential tracer for vesicular acetylcholine transporter (VAChT) which was enabled by this novel cross-coupling of [ 11C]MeLi.

Methods
[11C]MeLi was prepared via lithium-halogen exchange by trapping [11C]MeI in a solution of n-BuLi. The prepared [11C]MeLi was further reacted in a Pd catalyzed cross-coupling reaction with aryl bromides at r.t. for 4 minutes. After quench and evaporation of the solvent, the mixture was directly purified by HPLC. A series of synthesized vesamicol derivatives were subjected to affinity studies.

Scheme 1: Relevant structures for PET labelled via cross-coupling of [11C]MeLi

Results
Several clinically relevant structures with application in breast cancer imaging and early diagnosis of Alzheimer’s disease had been successfully labelled using this procedure (scheme 1). Employing this same methylation strategy, novel potential tracers for VAChT were synthesized and evaluated in vitro, identifying a compound with good selectivity for VAChT versus σ1 and σ2 and compared to established (-)FEOBV.

Table 1: In vitro affinities measured on rat VAChT (VAChT-PC12), n = 3; human σ1 (hS1-HEK293), n = 3; rat σ2 (rat liver), n = 2
Affinity (nM) (±)1-Me (±)2-Me (±)3-Me (-)3-Me (-)FEOBV
Ki(VAChT) 8.7 ± 0.1 7.2 ± 1.2 27 ± 18 28 ± 16 7 ± 2
Ki(σ1) 2.1 ± 0.5 5.3 ± 1.7 362 ± 36 382 ± 166 2275 ± 390
Ki(σ2) 373 ± 147 618 ± 257 1650 ± 650 >5000 2118 ± 1058
σ1/VAChT : σ2/VAChT 0.2 : 43 0.7 : 86 13 : 50 14 : >150 >300 : >300

Conclusion
A new labelling methodology was successfully applied to the synthesis of clinically interesting radiotracers, providing the purified target molecules in R.C.Y. ranging from 34% to 56% within 30 to 40 minutes (EOB). This procedure offers new opportunities in the development of novel tracers, illustrated by the synthesis of a novel VAChT tracer.

1Heijnen D, Tosi F, Vila C, Stuart M, Elsinga P, Szymanski W, Feringa B. Angew. Chem. Int. Ed. 2017, 56 (12), 3354-3359