3282 J. Med. Chem. 1994,37, zyxwvu 3282-3288 Technetium-99m N,"-Bis( 2-mercapto-2-methylpropyl)-2-aminobenzylamine: Technetium-99m Complexes of a Novel Bis(aminoethanethio1) Ligand Lynn C. Francesconi,? Yun Y. Yang, Mei-Ping Kung, Xiao X. Zhang, Jeffrey J. Billings, Yu-Zhi Guo, and Hank F. Kung* Department zyxwvutsrqpo of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 191 04, and Department of Chemistry, Hunter College of the City University of New York, New York City, New York 10021 Received April 14, 1994@ A new N2S2 ligand system, N~-bis(2-mercapto-2-methylpropyl)-2-aminobenzylamine, U-BAT, 1, containing uneven amine groups (two amine groups with different PKa values) for complexing [Tcv0l3+, was prepared. The reaction of this novel ligand with [99mTclpertechnetate, in the presence of stannous tartrate as the reducing agent, produces the neutral and lipid-soluble [99mTc]TcVO(U-BAT), TcSZC~~H~~N~O,~. However, when the same reaction was carried out at a higher pH, 9-10, and with 30 min of heating (100 "C), a second neutral but more lipid- soluble complex, [99mTc]TcVO(OU-BAT), TcS~C~~H~~N~O, 3, was isolated. The X-ray crystal- lography data of the 99Tc complexes show square pyramidal coordination with N2S2 as the base and the Tc=O in the apical position. Compound 3 can be derived from 2 by an oxidation of the ligand to form an imine. After iv injection into rats, the neutral and lipid-soluble technetium-99m complexes showed significant brain uptake, 1.54 and 1.07% dosejorgan at 2 min for [99mTclTcVO(U-BAT) and TcVO(OU-BAT), respectively. The novel Tc chemistry of this new ligand system may provide a useful foundation for designing Tc complexes with a built-in redox mechanism. Introduction The most commonly used radionuclide in diagnostic nuclear medicine is technetium-99m. Due to the physi- cal characteristics of technetium-99m (t112 zyxwvut = 6 h and y energy 140 keV) and the convenient availability from the 99MoP9mTc generator, most of the currently used scanning devices are optimized for detecting this radio- nuclide. There is a strong interest in developing tech- netium-99m chemistry in order to refine the biological properties of technetium-99m-labeled compounds. One of the ligand systems which has proven useful for forming a variety of stable [TcV0I3+ complexes is the bis(aminoethanethiol), BAT (N2S21, ligand (see Scheme 1). The BAT ligands are very robust and versatile in their coordination chemistry. N e ~ t r a l , ~ , ~ ~ationic,~ and an- ionic8~9 [TcV0I3+ complexes of N2S2 ligands have been formed. In addition, N2S2 ligands form neutral s7Cu2+ complexes and also complex with Ga3+ and In3+ l2 to form monocationic compounds.13 The overall net charges of the complexes are determined by the charge of the metal ion and also by the ionization at four possible sites, two S-H and two N-H (either as amines or amides) groups. It is important to recognize that the ionizability of the S-H and the amine or amide N-H groups determines the final net charge and, therefore, the ultimate biodistribution of these imaging agents. Scheme 1 illustrates the variable ionization sites for a number of recently reported N2S2 ligands and the corresponding Tc(O)N2S2 complexes. The diamide di- thiol ligand (DADT)*J4J5 forms a complex with [Tcv0l3+ which is negatively charged, due to complete ionization of the two S-H and two amide N-H groups; amide groups * Address correspondence to: Hank F. Kung, Ph.D., Department of Radiology, University of Pennsylvania, Room 305,3700 Market St., Philadelphia, PA 19104. Tel.: (215) 662-3096. Fax: (215) 349-5035. + Hunter College of the City University of New York. @ Abstract published inAdvance ACS Abstracts, September 1,1994. 0022-2623/94/1837-3282$04.50/0 Scheme 1. Comparison of [TcV0I3+ Complexes of Various NzSz (BAT) Ligands n n r 10 '(: /U'H If R L A [OOmT~]TM-BAT R: H [%"'Tc]NEP R: WN 3 0 aa SH Hs [="'Tc]ECD H EthyleneCysteine Dimer PIP nrl H-PIP n=2 [SBmT~]PIP n=l ["rc]H-PIP n=2 are more readily ionized compared to amines. Ligands with amine N-H groups form Tc complexes which are neutral and lipid-soluble.13J6 The S-H groups (PKa = 6-8) are ionized upon complexation with [TcvO13+; however, the amine N-H groups are usually not ionized or only partially ionized. The N2S2 (BAT)ligand forms 0 1994 American Chemical Society