Abstract: The liver-specific MRI contrast agent Gd-EOB-DTPA is used clinically to detect tumors in the liver. The ethoxybenzene (EOB) substituent confers hepatospecificity, as Gd-DTPA is not hepatospecific. Gd-EOB-DTPA has also been used experimentally to determine functional liver status via DCE-MRI. However, the analysis of this MRI-based data requires conversion of MRI signal enhancement to contrast agent concentration, a calculation fraught with error and experimental inaccuracies. We hypothesize that PET does a better job of directly providing tracer concentration than MRI, which can lead to more accurate diagnosis of early liver disease. Our goal was therefore to synthesize a hepatospecific PET compound for dynamic PET to measure liver function. First, we decided to use 64Cu as the radionuclide as it has the highest resolution of the PET radiometals, an important feature to measure image derived vascular input function. 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) is a macrocyclic, multidentate chelator with the capacity to form stable complexes with Cu2+. NOTA is a chelator that tolerates modifications and several NOTA-based bifunctional chelators (BFC) bearing reactive functional groups have been developed, possessing either carboxyl, amino or isothiocyanate groups for conjugation reactions with various biologically active molecules. We surmised that the appendage of the EOB moiety to 64Cu-NOTA to form 64Cu-EOB-NOTA would confer hepatospecific targeting. We synthesized EOB-NOTA from N, N-ditertiary butyl acetate of NOTA treated with 2-bromo-2-ethoxy benzyl tertiary butyl acetate in presence of base K2CO3/ACN at 80 oC furnished tritertiary butyl ester of EOB-NOTA which underwent the deprotection of tertiary butyl group in presence of KSF Clay gave the EOB-NOTA. Finally, it was radiolabeled with 64Cu radionuclide in high yield by addition of 64CuCl2 to free conjugate in buffered, aqueous solution. We validated the hepatobiliary transport of 64Cu-EOB-NOTA using PET in mice following intravenous injection. Peak uptake occurred at ~ 20 minutes, with slow washout over an hour. Measurement of 64Cu in the biological waste revealed a 50:50 hepatic:renal clearance of the agent.

Synthesis of 64Cu- EOB-NOTA: PET imaging of hepatocytes

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