The reaction of the racemic bis(amino thio)-phenylpiperidine compound BAT-PPP with "TcO," and stannous tartrate or TcvO(ethylene glycol^, resulted in two neutral isomeric complexes. In both complexes, the Tc is coordinated to an amide nitrogen atom, an amine nitrogen atom and both thiolate sulfur atoms in a square pyramidal coordination environment with oxygen in an apical position. The isomer with the pendant group syn to the Tc=0 bond appears to display longer retention time in reverse phase HPLC than the anti isomer. Both isomers were characterized in the solid state and in detailed NMR studies. The TcO(BAT-PPP) syn isomer (TcOCazHaeSaNjO) crystallizes in the monoclinic space group P2\/n, with Z = 4; the cell constants are a = 12.390(2) A,¿> = 11.470(2) A,c = 18.320(3) A, ß = 103.09(1)°, and V = 2534.92(69) Á3. The TcO(BAT-PPP) anti isomer (TCC22H36S2N3O) crystallizes in the orthorhombic space group Pna2\, with Z = 8; the cell constants are a = 19.823(2) Á, b = 11.530(2) Á, c = 22.373(4) Á, and V = 5114.17(15) Á3. The corresponding rhenium analogs were prepared by ligand exchange reactions. The ReO(BAT-PPP) syn isomer (ReC22H36S2N30) crystallizes in the monoclinic space group P2\/c with Z = 8, a = 17.681(2) A, b = 13.425(2) A, c = 21.301(4) A, ß = 99.81(1)°, and K = 4982.3(9) A3. The solution NMR data, taken in CDCI3, are consistent with the structures determined by X-ray diffraction experiments. The effects of the constrained ligand system and the M=0 group are clearly seen in the patterns for the syn and anti MO(BAT-PPP) (M = Tc, Re) isomers in proton and 13C NMR spectroscopy. The proton and 13C chemical shifts do not change significantly going from Tc to Re. Biodistribution differences between Tc isomers of BAT-PPP and isomers of a BAT ligand with a pendant biphenylylpiperizine (BPA) group may be rationalized in terms of the flexibility of the latter pendant group compared to the relative rigidity of the phenylpiperizine pendant group.
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A series of new p-alkylbenzamido derivatives of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p- iodobenzamido)ethyl]piperazines (p-MPPI) were prepared. In vitro binding studies suggest that p-methyl and p-ethyl substituents on the benzamido group display the same high binding affinity to 5-HT1A receptors (Ki = 2.2 and 9.3 nM, rat hippocampal homogenates). However, when the substitution groups were larger than a C5 pentyl group, the affinity to 5-HT1A receptors dropped below a useful level (Ki > 50 nM). Several irreversible binding agents (CH2Cl, NHCOCH2Cl) and a photoaffinity labeling compound (m-iodo p-azido) which showed good binding affinity to 5-HT1A receptors were successfully prepared.
In order to develop selective radioactive ligands for the study of presynaptic monoamine uptake sites, iodinated derivatives of tomoxetine were synthesized and evaluated in radioligand binding assays. Iodotomoxetine derivatives showed high affinity for serotonin (5-HT) uptake sites using a rat cortical membrane preparation. Compound 1R,(R)-(-)-N-methyl-3-(4-iodo-2-methylphenoxy)-3-phenylpropanamine , was the most potent and showed high stereoselectivity for 5-HT uptake sites (Ki, R isomer = 0.65 nM, S isomer = 13.9 nM). Changing the position of the methyl group or eliminating the methyl group at the phenoxy ring resulted in a loss of stereoselectivity. Substitution of the methyl group of tomoxetine with iodine gave the R and S isomers of N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine 4R and 4S. These compounds displayed stereoselectivity for the norepinephrine (NE) (Ki values = 0.24 and 9.35 nM for R and S isomers, respectively). The in vitro binding data suggest that 1R and 4R are potential radioiodinated ligands for pharmacological studies of 5-HT and NE uptake sites, respectively.
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