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Synthesis and Biologic Evaluation of 1-[¹¹C]-3,3-Dimethylheptadecanoic Acid

Massachusetts General Hospital Department of Radiology, Boston, Massachusetts
Northeastern University Medicinal Chemistry Section, Boston, Massachusetts

Correspondence: For reprints contact: David R. Elmaleh, PhD, Massachusetts General Hospital, Dept. of Radiology, Edwards Research Building, Rm. 517, Fruit St., Boston, MA 02114.

ABSTRACT

1-[¹¹C]-3,3-dimethylheptadecanoic acid ([¹¹C]DMHDA) has been prepared for evaluation as a potential myocardial metabolism indicator based on an expected intrinsic stability toward beta-oxidative metabolic processes. Synthesis of this novel branched-chain fatty acid was accomplished by copper-catalyzed addition of tetradecylmagnesium bromide to diethylisopropylidenemalonate. Subsequent saponification and decarboxylation afforded 3,3-dimethylheptadecanoic acid (DMHDA) that was converted to the corresponding alkyl bromide by means of a modified Hunsdiecker reaction. Carboxylation of 2,2-dimethylhexadecylmagnesium bromide with ¹¹CO₂ gave [¹¹C]DMHDA. Carbon-11 DMHDA showed moderate myocardial uptake in fasted rats, albeit lower than that reported for the 3-monomethyl analog. Considerable washout of radioactivity from the heart was also observed over the first 30 min postinjection. Imaging in dogs likewise showed disappointing heart uptake with much higher localization in the lung. These data suggest that gem-dimethyl substitution of the beta- position in long chain fatty acids is not only insufficient for enhanced myocardial uptake and retention, but also, may be deleterious when compared with betamonomethylation.