Appl. Radiur. hr. Vol. 43, No. 9, pp. 1151-1154, 1992 Inr. J. Radial. Appl. Ins~rum.Parr A Printed in Great Britain 0883-2889192 $5.00 + 0.00 Pergamon Press Ltd A New Neutral-Lipophilic 99m Tc Complex with a bis-Hydrazide-phosphine (BHP) Ligand K. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA V. KATTI’, P. R. SINGH’, W. A. VOLKERT’*, A. R. KETRING4 and K. K. KATT14 Departments of ’ Radiology and *Chemistry, 4 Research Reactor, University of Missouri and ’ Research Service, H.S. Truman Memorial VA Hospital, Columbia, MO 65211, U.S.A. (Received I8 Nooember 1991) A new bis-hydrazide-phosphine (BHP) ligand was synthesized, characterized and complexed with “mTc. %“‘Tc phenyl-BHP (PBHP) was shown to form a neutral-lipophilic chelate with %“Tc, in high yields, that is stable over a wide pH range. Results with 99”Tc-PBHP indicate that the BHP chelating moiety is attractive for use in designing nrw 99mTc-imaging agents. Introduction 99mT~ complexes that are neutral and lipophilic have been shown to hold potential for several applications in nuclear medicine ranging from their use as brain and myocardial perfusion imaging agents (Kung et al., 1990; Volkert, 1990; Pauwels et al., 1990; Morgan er al., 1990; Verbruggen, 1990) to their utility for cell labelling (Verbruggen, 1990; Dewanjee, 1990; Srivastava and Straub, 1990). 99mTc radiopharmaceu- ticals for assessing regional cerebral blood flow (rCBF) must be small in size to facilitate efficient passive diffusion across the intact blood-brain- barrier (BBB) (Kung et zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA al., 1990; Volkert, 1990; Pauwels et al., 1990). In contrast, larger neutral- lipophilic 99mTc chelates can be used for assessing myocardial blood flow (Nowotnik et al., 1990; Narra et al., 1989). To facilitate their utility for clinical studies, it is important that the 99mTc chelate be readily formed in high yields with high radiochemical purity (RCP). It is preferable to use 99mTcO; in 0.9% aqueous NaCl as a reactant since this form is rou- tinely available as the sterile-pyrogen free eluate from commercially available 99 Mo/99”Tc-generators. In the past years several new 99mTcchelates that are neutral and lipophilic chelates have been identified and each chelating system has its own unique chemi- cal and biological properties (Kung et al., 1990; Volkert, 1990; Pauwels et al., 1990; Morgan et al., 1990; Verbruggen, 1990). New 99mTc chelates of this type may provide a vehicle for development of im- proved agents. To this end, a new 99mTc chelate was identified that employs the bis-hydrazide-phosphine *Author for correspondence. (BHP) [Fig. I] chelating moiety to form a stable neutral-lipophilic complex in high yields by a one step reaction with 99”Tc0;. Experimental Synthesis of (HJV-NMe),P(S)Ph A solution of methyl hydrazine (10.23 g; 222 mmol) in CHCI, (100 mL) was added dropwise to a solution of phenylphosphonothionic dichloride (Aldrich Chemical Co.) (9.13 g; 37 mmol) also in 100 mL of CHCI, maintained at 0°C. The reaction mixture was stirred for I2 h at 25°C and refluxed for 2 h before it was cooled and filtered. The fitrate was evaporated to dryness in uacuo. The white solid residue was recrys- tallized in CH, CN to obtain analytically pure phenyl- BHP (PBHP) in 92% yield m.p. 97°C. Anal. calcd for C,H,,N,PS: C, 41.73; H, 6.52; N, 24.30. Found: C, 41.59; H, 6.52; N, 24.27. ‘H-NMR (CDCl,; SiMe,) phenyl ring S 7.32 (m, 5H); NCH,, 6 2.92 (d, 6H; ‘JP-H = 11.90 Hz); 6 NH,, 6 3.65 (s, broad, 4H). “P-NMR (CDCI,; 85% H,PO,) 6 “P 86.50 (s). Complexation methods 99”Tc-PBHP was formed by the addition of 0.1 mL of 0.9% aqueous NaCl (saline) containing 2-3 MBq/mL of 99mTcO; and 0.9 mL of I mg PBHP/mL in 0. I N HCI to 4.0 mL saline. The 99mTc0; solutions were prepared by dilution of the eluant from a 99Mo/99mT~ generator (Mallinckrodt Nuclear) with 0.9% aqueous NaCl (saline). This mixture was incu- bated for various times at room temperature (~22’C), 75°C and 100°C (i.e. in a boiling water bath). II51