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-ribo se) from NAD+, thereby releasing the DNA from histones to a transcript ionally 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-aminoben zamide, 3-methoxybenzamide and nicotinamide were labelled with carbon- 11 in the amide group. Starting with the corresponding aromatic halide s and hydrogen [C-11]cyanide, the substituted [C-11]benzonitrile's wer e prepared using a palladium promoted reaction. Conversion of the nitr iles to [carboxy-C-11]amides was achieved by reaction with sodium perc arbonate. A one-pot procedure for the synthesis of the C-11-labelled a romatic amides was developed. The total synthesis time including rever sed-phase HPLC purification was 25-35 min. Decay-corrected radiochemic al yield was 45-70% and the radiochemical purity >99%. The specific ra dioactivity was in the order of 2-3 Ci . mumol-1. Initial distribution and kinetic studies were performed in monkey using the tracer substan ce injected as a rapid bolus. These studies demonstrated that the bloo d-clearance was fast for [carboxy-C-11]nicotinamide but considerably s lower for 3-amino[carboxy-C-11]benzamide and 3-methoxy[carboxy-C-11]be nzamide. The brain uptake was low for all substances except 3-methoxy[ carboxy-C-11]benzamide which initially had a high brain uptake, follow ed 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.