Effects of configuration on the myocardial uptake of radioiodinated 3(R)-BMIPP and 3(S)-BMIPP in rats

Radioiodinated 3(R)-(+)- and 3(S)-(-)-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) were prepared and evaluated in rats to investigate the effects of absolute configuration of the 3(beta)-methyl group on myocardial uptake and release kinetics.

The 3(R)-(+)-BMIPP analog was synthesized by initial acylation of a thiophene template with the acid chloride of ethyl 3(R)-methylglutarate. 3(S)-(-)-BMIPP was obtained by separation from the mixture of diastereomeric amides prepared from reaction of the acid chloride of racemic BMIPP with the S-(-)-alpha-methylbenzylamine. The amide of synthetic 3(R)-BMIPP prepared from S-(-)-alpha-methylbenzylamine was identical to the chromatographically more polar isomer. Free acids were obtained by acid hydrolysis of the amides, fully characterized and then converted to the radioiodinated BMIPP isomers.

Biodistribution studies in rats with the dual-labeled [(131)I]-3(S)-BMIPP/[(125)I]-3(R)-BMIPP mixture demonstrated greater myocardial uptake of 3(R)-BMIPP compared with the 3(S)-BMIPP isomer [60 min: 3(R)-BMIPP = 4.37 %ID/g; 3(S)-BMIPP = 3.44; p < 0.05; 180 min, 2.31 and 1.78 %ID/G, respectively, p < 0.01], although both isomers had similar myocardial washout curves (5-180 min). Percent ID/g values for other tissues which were examined (blood, lungs, thyroid) were similar.

Higher myocardial uptake of the 3(R)-BMIPP isomer observed in these animal studies may suggest differences in carrier-mediated myocyte uptake of the two isomers. These studies suggest that [(123)I]-3(R)-BMIPP is a candidate for clinical evaluation and may show greater myocardial uptake than the 3(S)-BMIPP isomer and may thus require reduced injected dose.