Development of novel mixed-ligand oxotechnetium [SNS/S] complexes as potential 5-HT1A receptor imaging agents

The "3+1" ligand system [SN(R)S/S combination] was applied in order to synt hesize neutral mixed-ligand oxotechnetium complexes of the general formula (99)mTcO[SN(R)S]/[S] as potential 5-HT1A receptor imaging agents. The compl exes are carrying the 1-(2-methoxyphenyl)piperazine moiety, a fragment of t he true 5-HT1A antagonist WAY 100635, either on the monodentate ligand [S] or on the tridentate ligand [SN(R)S]. The complexes MO[EtN(CH2CH2S)(2)] [o- MeOC6H4N(CH2CH2)(2)NCH2CH2S] (3), MO[o-MeOC6H4N(CH2CH2)(2)N(CH2)(3)N(CH2CH2 S)(2)][PhS] (6) and MO[o-MeOC6H4N(CH2CH2)(2)N(CH2)(3)N(CH2CH2S)(2)] [PhCH2C H2S] (9), where M=(99)mTc, were prepared at tracer level using (99)mTc gluc oheptonate as precursor. For structural characterization. the analogous oxo rhenium (M=Re, 1, 4 and 7, respectively) and oxotechnetium (M=Tc-99g, 2, 5 and 8, respectively) complexes were prepared by ligand exchange reactions. All products were characterized by elemental analysis and spectroscopic met hods. Complexes 1, 4 and 7 were further characterized by crystallographic a nalysis. For 1, the coordination geometry about rhenium can be described as trigonally distorted square pyramidal (tau =0.36), while for 4 and 7, as d istorted trigonal bipyramidal (tau =0.66 and tau =0.61, respectively). The coordination sphere about oxorhenium in all complexes is defined by the SNS donor atom set of the tridentate ligand and the sulfur atom of the monoden tate coligand. The structure of the Tc-99m complexes 3, 6 and 9 was establi shed by comparative HPLC using authentic oxorhenium and oxotechnetium sampl es. The binding affinity of oxorhenium compounds for the 5-HT1A receptor su btype was determined in rat brain hippocampal preparations (IC50=6-31 nM). Preliminary tissue distribution data in healthy mice revealed the ability o f all three Tc-99m complexes to cross the intact blood-brain barrier (0.49- 1.15% ID at 1 min p.i.). In addition, complexes 6 and 9 showed significant brain retention. These promising results have demonstrated that the SNS/S m ixed-ligand system can be used in the development of Tc-99m complexes as po tential 5-HT1A receptor imaging agents.