Radioiodinated 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid: a useful new agent to evaluate myocardial fatty acid uptake

Abstract

Radioiodinated 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP) has been prepared as a new terminal iodophenyl-substituted fatty acid containing dimethyl-branching at the beta position. For the synthesis of this new agent, chain homologation was accomplished by fabrication of a 2,5-disubstituted thiophene by successive Friedel-Crafts acylation and Wolff-Kishner reduction reactions, followed by thiophene ring opening. The dimethyl-branching was introduced using the monomethyl ester of dimethylglutaryl chloride. Radioiodination of the 15-phenyl-3,3-dimethylpentadecanoic acid substrate in the para position then gave DMIPP. Iodine-125-labeled DMIPP showed rapid, high myocardial uptake (min, mean % injected dose/g) in fasted rats (5, 4.67; 30, 5.06; 60, 4.79; 120, 4.37), and also exhibited good heart:blood ratios (min, heart:blood: 5, 3:1; 30, 12:1; 60, 12:1; 120, 13:1). To further evaluate the effects of dimethyl-branching, the biodistribution properties of DMIPP were compared with the 3-monomethyl-branched (15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid; BMIPP) and the unbranched (15-(p-iodophenyl)pentadecanoic acid; IPP) analogs. A triple-labeled [123I]DMIPP/[131I]BMIPP/[125I]IPP mixture was administered to groups of fasted rats. These results confirmed the greater myocardial retention and higher heart:blood ratios observed with DMIPP in comparison with both the 3-monomethyl-(BMIPP) and unbranched (IPP) analogs. These data suggest that [123I]DMIPP is an excellent candidate for clinical evaluation of regional energy substrates (fatty acid) uptake.