SYNTHESIS OF C-11 LABELED BENZAMIDE COMPOUNDS AS POTENTIAL TRACERS FOR POLY(ADP-RIBOSE) SYNTHETASE

Poly (ADP-ribose) synthetase catalyses the synthesis of poly (ADP-ribose) from NAD+, thereby releasing the DNA from histones to a transcriptionally and reparationally active form. In order to investigate if in vivo and in vitro studies of this enzyme are feasible to perform with PET, the poly (ADP-ribose) synthetase inhibitors benzamide, 3-aminobenzamide, 3-methoxybenzamide and nicotinamide were labelled with carbon-11 in the amide group. Starting with the corresponding aromatic halides and hydrogen [C-11]cyanide, the substituted [C-11]benzonitrile's were prepared using a palladium promoted reaction. Conversion of the nitriles to [carboxy-C-11]amides was achieved by reaction with sodium percarbonate. A one-pot procedure for the synthesis of the C-11-labelled aromatic amides was developed. The total synthesis time including reversed-phase HPLC purification was 25-35 min. Decay-corrected radiochemical yield was 45-70% and the radiochemical purity >99%. The specific radioactivity was in the order of 2-3 Ci . mumol-1. Initial distribution and kinetic studies were performed in monkey using the tracer substance injected as a rapid bolus. These studies demonstrated that the blood-clearance was fast for [carboxy-C-11]nicotinamide but considerably slower for 3-amino[carboxy-C-11]benzamide and 3-methoxy[carboxy-C-11]benzamide. The brain uptake was low for all substances except 3-methoxy[carboxy-C-11]benzamide which initially had a high brain uptake, followed by a rapid wash-out. The C-11-labelled nicotinamide demonstrated a rapid fixation with high uptake values in the liver, kidney and lymph nodes.