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

A rapid route for the synthesis of radiolabelled t-PA(stop) 8, an efficient serine protease inhibitor, is described. (E,E)-2,7-Bis(4-iodobenzylidene)c ycloheptan-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) tellurox ide (BMPTO). These methods are general and have been successfully applied t o the high yielding preparation of other aldol adducts such as 2b and 2c. T he two step transformation of (E,E) 2a into the asymmetric (Z,Z)-2-(4-cyano benzylidene)-7-(4-iodobenzylidene)cycloheptan-1-one 5 has been optimized. T he radiochemical yield for the radiolabelling of 5 with K[(CN)-C-11] follow ed by palladium catalysis to give the labelled bisnitrile 7 was 80-90%. A s eries of experiments with various methods is reported and the first procedu re for the preparation of [C-11]amidines from the corresponding [C-11]bisni triles with N-acetylcysteine is presented; the radiochemical yield, based o n analytical liquid chromatography was 80% for the radioamidination. [C-11] 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%.