A Tc-99m-labeled long chain fatty acid analog metabolized by the heart

Abstract

1888

Objectives: Development of ^99mTc-labeled long chain fatty acid analogues metabolized by beta-oxidation in myocardium still constitutes an unsettled challenge. A recent study showed that [¹⁸⁸Re]tricarbonyl (carboxycyclopentadienyl) rhenium was recognized as an aromatic compound and metabolized as such by the body. Based on these findings, cyclopentadienyltricarbonyltechnetium (CpTT) was conjugated to the ω-position of pentadecanoic acid to prepare CpTT-PA. Biodistribution and myocardial metabolism of CpTT-PA were investigated in rats to estimate the chemical design for developing ^99mTc-labeled fatty acid analog.

Methods: The ferrocene precursor, 15-ferrocenoyl- tetradecanoic acid methyl ester was prepared by Friedel-Crafts reaction using ferrocene and 1-methyl pentadecanoic acid chloride in the presence of AlCl₃. CpTT-PA was prepared by the double ligand transfer reaction of the ferrocene precursor with ^99mTcO₄^-, followed by the reduction of acyl-CpTT to alkyl-CpTT and subsequent hydrolysis of the methyl ester. The chemical structure of CpTT-PA was confirmed by HPLC using well-characterized rhenium compound as a reference. Biodistribution studies were performed after intravenous injection of CpTT-PA to rats. SPECT images were also taken after injection of CpTT-PA to rats. Myocardial metabolism of CpTT-PA was assessed using the isolated Langendorff-perfusded rat heart model.

Results: CpTT-PA was obtained with radiochemical yield and purity of 10.1 % and over 93 %, respectively. When injected to rats, CpTT-PA exhibited the highest myocardial accumulation of 3.85 %ID/g at 1 min postinjection, followed by a gradual decrease with times. Due to the faster clearance of radioactivity from the blood, CpTT-PA registered the heart- to-blood ratios of radioactivity of 2.93, 4.60 and 3.44 at 5, 10 and 30 min postinjection. Myocardial accumulation of CpTT-PA was also confirmed by SPECT studies. The metabolic study using isolated Langendorff-perfused rat hearts demonstrated that the major radiometabolite in the perfusate and in the myocardium had a retention time identical to that of 4-cyclopentadienyltricarbonyltechnetium butyric acid, the metabolite after six cycles of beta-oxidation of CpTT-PA.

Conclusions: CpTT-PA exhibited significant myocardial accumulation and heart-to-blood ratios of radioactivity, which visualized rat myocardium by SPECT. CpTT-PA was also recognized as a substrate for beta-oxidation by the myocardium. These findings indicated that CpTT-PA would constitute a potential candidate for SPECT-based myocardial metabolic studies.