Synthesis of N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-[11C]carboxamide ([11C-carbonyl]PK11195) and some analogues using [11C]carbon monoxide and 1-(2-chlorophenyl)isoquinolin-3-yl triflate

Abstract

The benzodiazepine receptor ligand, N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide (PK11195), and five structurally related analogues were ¹¹C-labelled via a palladium-mediated carbonylation using [¹¹C]carbon monoxide, 1-(2-chlorophenyl)isoquinolin-3-yl trifluoromethanesulfonate and various amines. The ¹¹C-labelled products were obtained with decay-corrected radiochemical yields in the range of 10–55% and with high specific radioactivity (e.g. 200–900 GBq µmol⁻¹). The radiochemical purity of the final products exceeded 98%. In a typical experiment starting with 3.75 GBq [¹¹C]carbon monoxide, 0.57 GBq of LC-purified products were obtained within 35 min of the start of the carbonylation reaction. For confirmation of the labelling position, N-(1-methylethyl)-1-(2-chlorophenyl)-isoquinoline-3-(¹³C)carboxamide was prepared and analysed by NMR. The precursor 1-(2-chlorophenyl)isoquinolin-3-yl trifluoromethanesulfonate was synthesised in five steps starting from 2-chlorobenzophenone. The precursor N-methyl-sec-butylamine was prepared from sec-butylamine by the reaction with ethyl chloroformate followed by reduction with LiAlH₄. The non-radioactive reference compounds for the analogues were synthesised from 1-(2-chlorophenyl)isoquinoline-3-carboxylic acid and the appropriate amines.