Evaluation of radioiodinated medium chain fatty acids as new diagnostic agents for the determination of hepatic viability

Abstract.

Radiopharmaceuticals which reflect beta-oxidation in hepatocytes will provide useful information on the prognosis after surgery or on the efficacy of treatment, since beta-oxidation is the main pathway responsible for adenosine triphosphate in hepatocytes. We have previously developed [1-¹¹C]octanoate as a diagnostic agent for determination of hepatic viability by means of positron emission tomography (PET). The goal of the present study was to develop a new radiopharmaceutical for single-photon emission tomography (SPET), which has the advantage of being more widely used than PET. To this end, two radioiodinated ω-(4-iodophenyl)-medium chain fatty acids, p-iodophenylvaleric acid (IPVA) and p-iodophenylenanthic acid (IPEA), were synthesized and evaluated as radiopharmaceuticals for determination of hepatic viability. Metabolite analyses in vitro and in vivo and a biodistribution study in normal mice indicated that both compounds were taken up by the liver actively and metabolized by beta-oxidation. However, these studies also indicated that IPEA is more suitable as an imaging agent than IPVA. Based on these results, SPET imaging studies were performed in normal and hepatitis model rats using [¹²³I]IPEA. The time-activity curves of the liver showed two-phase clearance of radioactivity in both normal and hepatitis model rats, but the clearance was delayed depending on the severity of hepatitis. Furthermore, the clearance rate of the first phase was correlated with the ATP level in hepatocytes, which was used as an index of the energy production capacity of hepatocytes. In conclusion,IPEA was metabolized predominantly by beta-oxidation, and the clearance of IPEA from the liver was closely associated with the ATP concentration in the liver. Thus, [¹²³I]IPEA is a potentially useful new radiopharmaceutical for diagnosis of hepatic viability based on energy metabolism.