STRUCTURE-ACTIVITY-RELATIONSHIPS FOR METAL-LABELED BLOOD-FLOW TRACERS - COMPARISON OF KETO ALDEHYDE BIS(THIOSEMICARBAZONATO)COPPER(II) DERIVATIVES

Radiocopper-labeled pyruvaldehyde bis (N4-methylthiosemicarbazonato) copper (II), Cu[PTSM], is under investigation as a radiopharmaceutical for evaluation of regional blood flow in the brain, heart, and kidneys because it affords relatively high levels of radioactivity in these organs upon intravenous injection, followed by prolonged tissue retention of the radiolabel. To probe and differentiate the physicochemical properties that are critical for blood-brain barrier (BBB) penetration and tissue retention in complexes of this type, 17 64Cu-labeled copper(II) bis(thiosemicarbazone) derivatives of Cu[PTSM] have been prepared and characterized, focusing on the bis(thiosemicarbazone), bis-(N4-methylthiosemicarbazone), bis(N4-dimethylthiosemicarbazone), and bis(N4-ethylthiosemicarbazone) derivatives of several alkylglyoxals (R(1)= Me, Et, n-Pr, i-Pr, n-Bu, or Me(EtO)CH) and phenylglyoxal. The compounds studied varied in lipophilicity from log P = 0.75 to log P = 3.5 (where P is the octanol/water partition coefficient). In rat biodistribution studies the N4-methylthiosemicarbazone (R(1)TSM) and N4-dimethylthiosemicarbazone (R(1)TSM2) complexes always show comparable cerebral uptake at 1 min postinjection (iv) for any given R(1) group, while the thiosemicarbazone (R(1)TS) complex always penetrates the BBB less efficiently. Comparison of the various Cu[R(1)TS] derivatives shows that their brain uptake does tend to increase with increasing lipophilicity over the range 0.75 < log P < 2.4, although it never reaches that of the N4-alkylated derivatives. The Cu[R(1)TS] and Cu[R(i)TSM] complexes are found to exhibit prolonged cerebral retention of activity, consistent with their known susceptibility to reductive decomposition by intracellular sulfhydryl groups, while the more inert Cu[R(X)TSM2] complexes clear from the brain relatively rapidly. Tracer clearance kinetics in the heart and kidney are similar to those observed for the brain with each of the tracers examined. © 1990, American Chemical Society. All rights reserved.