Synthesis and Characterization of Oxotechnetium(V) Mixed-Ligand Complexes Containing a Tridentate N-Substituted Bis(2-mercaptoethyl)amine and a Monodentate Thiol.

A series of 22 mixed-ligand complexes of the general formula TcOL(1)L(2), where L(1)H(2) are N-substituted bis(2-mercaptoethyl)amine ligands, [SN(R)S], and L(2)H are monodentate thiols as coligand, is reported. The complexes were prepared by the ligand exchange method using Tc-gluconate as precursor and equimolar quantities of the two ligands. In all cases the syn stereoisomer was formed in high yield and isolated as a crystalline product. In four cases HPLC analysis demonstrated the presence of the anti stereoisomer in the reaction mixture. Although the yield was less than 1%, one anti isomer, 4a, was successfully isolated as brown crystals. The isolated complexes were characterized by spectroscopic methods and elemental analysis. The formation of the two diastereomers, syn and anti, was expected due to the configuration of the nitrogen substituent (R) with respect to the central TcO core. The X-ray crystallography showed that the coordination geometry of the syn isomers 9, 11, and 18 is trigonal bipyramidal while for the anti isomer 4a it is distorted square pyramidal. This is the first documentation of syn/anti isomerism in N-substituted TcO[SN(R)S][S] mixed-ligand complexes.

Tridentate ligands containing the SNS donor atom set as a novel backbone for the development of technetium brain-imaging agents.

In developing 99mTc complexes as potential brain-imaging agents, we investigated the coordination chemistry of ligands containing sulfur and nitrogen donor atoms with the general formula R-CH2CH2N(CH2CH2SH)2 (R = C2H5S, (C2H5)2N). These ligands act as tridentate SNS chelates to the TcO3+ core, leaving open one coordination site cis to the oxo group. In reactions with the highly reactive [99TcOCl4]- precursor, this vacancy was occupied by a chlorine atom. When the ligands reacted in the presence of 4-methoxythiophenol, using 99Tc(V)-gluconate as precursor, the vacancy was filled with 4-methoxythiophenol, which acted as coligand. Thus neutral mixed ligand complexes of the general formula [TcO((SCH2CH2)2NCH2CH2R)X], where X = Cl or 4-methoxythiophenol, were synthesized. The complexes were characterized by UV-vis, IR, 1H NMR, crystallographic, and elemental analyses. The crystal structures of 3a (R = C2H5S, X = Cl) and 4b (R = (C2H5)2N, X = 4-methoxythiophenol) demonstrated that the coordination geometry is trigonal bipyramidal with the N1 and Cl or S3 occupying the apical positions and the basal plane defined by the S1 and S2 of the tridentate ligand and the oxo group. The complexes 4a(99mTc) (R = C2H5S, X = 4-methoxythiophenol) and 4b(99mTc) were prepared using 99mTc-glucoheptonate as precursor and were purified by HPLC. Biodistribution in mice showed high initial brain uptake (3.68% and 3.56% dose/organ for 4a(99mTc) and 4b(99m-Tc), respectively). Complex 4b(99mTc) displayed significantly higher brain/blood values and prolonged retention in brain as well. The results suggest that structural modifications based on configurations 4a,b may provide novel 99mTc brain-imaging agents with improved biological characteristics.

Renal elimination of some 99mTc-labelled cysteamine derivatives.

It is generally believed that -CO-NH-(CH2)n-COOH moiety promotes tubular excretion of organic anions. Recently it was reported that newly developed renal agents, containing the oxotechnetium(V) glycine group, may mimic the carbonyl amide sequence of [131]I-o-iodohippuric acid. In this study the renal excretion of certain carboxy-cysteamine derivatives is investigated in mice, in the presence of renal tubular transport inhibitor. A similar pattern of renal depression was observed for complexes containing the oxotechnetium glycine sequence, suggesting that this group may satisfy structural parameters for tubular secretion of anionic technetium complexes.

Correlation of lipophilicity to biodistribution of 99mTc-labelled aminothiols.

A series of 99mTc-DADT complexes substituted with heterocyclic amines were synthesized and tested for their ability to cross the BBB. Each 99mTc-DADT complex analysed by HPLC was found to consist of two epimers. The more lipophilic epimers were biodistributed in mice. The data demonstrated a significant brain uptake (3-12% dose/g whole brain) and a high lung accumulation (11-85% dose/g) at 2 min p.i. Between the partition coefficients of the technetium complexes, a linear correlation for lung accumulation was observed, while a parabolic curve for brain uptake was found.

99mTc-DADT complexes substituted with heterocyclic amines: effect of substitution on in vivo reactivity.

Alkylpiperidinyl and alkylpyrrolidinyl 99mTc-DADT complexes were synthesized and tested for their ability to cross the BBB. Each complex was a mixture of two epimers separated by HPLC. More lipophilic epimers were biologically evaluated in mice, at various time intervals. Similar biodistribution patterns were obtained for both piperidinyl and pyrrolidinyl DADT-complexes. Brain uptake or retention was influenced by the heterocyclic amine introduced into the DADT backbone. Subcellular concentration of selected 99mTc-DADT complexes was more profound in crude nuclear and post-microsomal fractions. Moreover, interaction of 99mTc-2,2,6,6,9,9-hexamethyl-4,7-diaza-4-(3-methylpyrroli dinyl)-ethyl-1,10- decanedithiol with either lipids or microsomes of whole brain was almost unaffected by time. This may suggest that a possible selective site of interaction and metabolism for DADT complexes occurs in brain.