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.