IMPORTANCE OF THE 2 ESTER FUNCTIONS FOR THE BRAIN RETENTION OF TC-99M-LABELED ETHYLENE DICYSTEINE DIETHYL ESTER (TC-99M-ECD)

Tc-99m-ethylene dicysteine diethyl ester (Tc-99m-L,L-ECD) is a neutral lipophilic tracer agent that crosses the blood-brain barrier and is r etained in the brain of primates following enzymatic hydrolysis of one of the ester functions to the ionized mono-ester, mono-acid metabolit e. Up to now, it is not clear whether the second ethylcarboxylate grou p is essential for brain uptake and retention. Therefore, we have synt hesized and studied two derivatives of Tc-99m-L,L-ECD that contain onl y one ethylcarboxylate function, namely Tc-99m-labelled L- and D-ethyl ene cysteamine cysteine ethyl ester (Tc-99m-ECCE). Direct labelling of L- or D-ECCE at neutral pH and room temperature resulted for each of them in the formation of two probably diastereomeric Tc-99m complexes in a 1:1 ratio. This means that four different isomers could be isolat ed. The Tc-99m-labelled complexes formed after labelling ECCE (A and B , in order of elution during HPLC) are slightly less lipophilic than T c-99m-L,L-ECD. In mice, all four isomers show a low brain activity at 10 min post injection (p.i.), approximately 0.1% to 0.3% of the inject ed dose versus 0.9% for Tc-99m-L,L-ECD, The clearance from the blood i s comparable with (isomers LA and LB) or slower (isomers DA and DB) th an that of Tc-99m-L,L-ECD, Isomers LA and DA show high liver uptake an d rapid excretion to the intestines. Both Tc-99m-ECCE-LB and Tc-99m-EC CE-DB, the most lipophilic isomers, are cleared from the blood mainly by the kidneys and excreted more efficiently to the urine. Tc-99m-ECCE -LB is characterized by a surprisingly high heart uptake (about 1.5% o f i.d.) at 10 min p.i. versus 1.0% for Tc-99m-methoxyisobutylisonitril e (Tc-99m-MIBI) and 0.2-0.3% for the other isomers, but also lung upta ke is relatively high. In the baboon, brain and heart uptake of isomer s LA and LB of Tc-99m-ECCE were negligible, Activity concentrated most ly in the hepatobiliary system for isomer LA and in the renal system f or isomer LB, The results indicate a clear difference in biological be haviour between Tc-99m-L,L-ECD and the four isomers of Tc-99m-ECCE. Th is shows that the presence of both ester functions in Tc-99m-L,L-ECD i s an essential structural requirement for its brain uptake and retenti on in primates. NUCL MED BIOL 25;6:569-575, 1998. (C) 1998 Elsevier Sc ience Inc.