Neutral and stereospecific Tc-99m complexes: [Tc-99m]N-benzyl-3,4-di-(N-2-mercaptoethyl)-amino-pyrrolidines (P-BAT)

Technetium-99m-labeled radiopharmaceuticals are currently the most commonly used agents in nuclear medicine. To prepare binding site-specific small mo lecules containing a Tc-99m complexing core, it is important to consider a ligand system, which selectively forms only one stereoisomer. A novel serie s of bisaminoethanethiol (BAT) derivatives as a model system were prepared. Stereoisomers of N-benzyl-3,4-di(N-2-mercaptoethyl)-amino pyrrolidines (P- BAT): (3R,4R)-P-BAT (R,R-4) and (3,4)meso-P-BAT (8), the trans and meso iso mer, respectively, as a chelating group were prepared successfully, The des ired Tc-99m P-BAT complexes were obtained by using Sn(II)/glucoheptonate as the reducing agent for [Tc-99m]pertechnetate. As predicted, after complexa tion with [Tc-99m](TcO)-O-v, the trans isomer, (3R,4R)-P-BAT (R,R-4), showe d only one isomer; whereas the corresponding meso isomer, (3,4)meso-P-BAT ( 8), produced two distinctive complexes isolated readily by high performance liquid chromatography (HPLC). The [Tc-99m](R,S) meso-P-BAT (8) isomers sho wed a different lipophilicity (partition coefficient [P.C.] = 54.3 and 55.4 for peak A and peak B, respectively), as compared with that of the corresp onding [Tc-99m](3R,4R) -P-BAT (R,R-4), trans isomer (P.C. = 163). Results o f the biodistribution study in rats of these isomers show different heart a nd brain uptake, suggesting that the intrinsic differences in biodistributi on are due to structural and stereospecific factors. Examples in this repor t confirm that it is possible to design stereospecific Tc-99m complexes bas ed on the bisaminoethanethiol (N2S2, BAT) ligand system. Consideration on s tereoselectivity of site-specific agents labeled with Tc-99m is likely an e ssential requirement on developing binding-site specific radiopharmaceutica ls. NUCL MED BIOL 26;2:217-224, 1999. (C) 1999 Elsevier Science Inc. All ri ghts reserved.