Total synthesis and radiolabelling of an efficient rt-PA inhibitor: [11C] (Z,Z)-BABCH. A first route to [11C] labelled amidines

Abstract

A rapid route for the synthesis of radiolabelled t-PA_stop8, an efficient serine protease inhibitor, is described. (E,E)-2,7-Bis(4-iodobenzylidene)cycloheptan-1-one 2a was obtained in high yields (>90%) from cycloheptanone and 4-iodobenzaldehyde, with the unprecedented use of CsOH or by microwave irradiation using catalytic amounts (<20%) of bis(methoxyphenyl) telluroxide (BMPTO). These methods are general and have been successfully applied to the high yielding preparation of other aldol adducts such as 2b and 2c. The two step transformation of (E,E) 2a into the asymmetric (Z,Z)-2-(4-cyanobenzylidene)-7-(4-iodobenzylidene)cycloheptan-1-one 5 has been optimized. The radiochemical yield for the radiolabelling of 5 with K[¹¹CN] followed by palladium catalysis to give the labelled bisnitrile 7 was 80–90%. A series of experiments with various methods is reported and the first procedure for the preparation of [¹¹C]amidines from the corresponding [¹¹C]bisnitriles with N-acetylcysteine is presented; the radiochemical yield, based on analytical liquid chromatography was 80% for the radioamidination. [¹¹C]t-PA_stop was isolated in a radiochemical yield ranging from 50 to 60% in 55 min overall and with a radiochemical purity higher than 95%.