Glutathione-Mediated Metabolism of Technetium-99m SNS/S Mixed Ligand Complexes: A Proposed Mechanism of Brain Retention

Two series of [99mTc](SNS/S) mixed ligand complexes each carrying the N-diethylaminoethyl or the N-ethyl-substituted bis(2-mercaptoethyl)amine ligand (SNS) are produced at tracer level using tin chloride as reductant and glucoheptonate as transfer ligand. The identity of [99mTc](SNS/S) complexes is established by high-performance liquid chromatographic (HPLC) comparison with authentic rhenium samples. The para substituent R on the phenylthiolate coligand (S) ranges from electron-donating (−NH2) to electron-withdrawing (−NO2) groups, to study complex stability against nucleophiles as a result of N- and R-substitution. The relative resistance of [99mTc](SNS/S) complexes against nucleophilic attack of glutathione (GSH), a native nucleophilic thiol of 2 mM intracerebral concentration, is investigated in vitro by HPLC. The reaction of [99mTc](SNS/S) complexes with GSH is reversible and advances via substitution of the monothiolate ligand by GS- and concomitant formation of the hydrophilic [99mTc](SNS/GS) daughter compound. The N-diethylaminoethyl complexes are found to be more reactive against GSH as compared to the N-ethyl ones. Complex reactivity as a result of R-substitution follows the sequence −NO2 ≫ −H > −NH2. These in vitro findings correlate well with in vivo distribution data in mice. Thus, brain retention parallels complex susceptibility to GSH attack. Furthermore, isolation of the hydrophilic [99mTc](SNS/GS) metabolite from biological fluids and brain homogenates provides additional evidence that the brain retention mechanism of [99mTc](SNS/S) complexes is GSH-mediated

New Oxorhenium(V) Complexes from the Widely Used Diaminedithiol (DADT) Ligand System

Synthesis of the 2,9-dimethyl-4,7-diaza-4-alkyl-2,9-decanedithiol (1, alkyl = morpholinylethyl in a, and alkyl = pyrrolidinylethyl in b), following a widely used synthetic scheme for diaminedithiol (DADT) ligands, led to the isolation of 1-alkyl-2-(1‘-methyl-1‘-sulfanylethyl)-3-(2‘ ‘-methyl-2‘ ‘-sulfanylpropyl)diazolidine (3) as the major product. Both ligands 1 and 2 gave complexes with the oxorhenium ReO(V) core. Ligand 1 gave the expected ReO[SNNS] complex (2) with the side chain on nitrogen in the syn configuration. Ligand 3 gave, in the presence of a monodentate aromatic thiol, complexes of the ReO[SNN][S][S] (4) and ReO[SNN][S] type (5), respectively, in which the diazolidine ring has rearranged to a thiazolidine ring. Crystallographic analysis showed that in 4 the coordination geometry about the metal is distorted octahedral where the equatorial plane is defined by the sulfur and one of the nitrogen atoms of the ligand and the two sulfurs of the aromatic thiols, while the axial positions are occupied by the oxygen of the ReO core and the second nitrogen of the ligand. Specifically, complex 4a crystallizes in space group P21/c, a = 15.63(1) Å, b = 15.28(2) Å, c = 16.07(1) Å, β = 113.78(2)°, V = 3512(5) Å3, Z = 4. Complex 4b crystallizes in space group P21/n, a = 14.560(9) Å, b = 14.804(9) Å, c = 19.85(1) Å, β = 90.94(2)°, V = 4278(1) Å3, Z = 4. In 5b, the coordination geometry is distorted square pyramidal with the SNN donor atom of the ligand and the aromatic thiol defining the equatorial plane and the doubly bonded oxygen occupying the apex of the pyramid. Complex 5b crystallizes in space group P1̄, a = 9.387(5) Å, b = 11.306(5) Å, c = 14.040(6) Å, α = 84.51(1)°, β = 84.45(2)°, γ = 87.17(1)°, V = 1475(1) Å3, Z = 2. All isolated complexes are neutral and lipophilic. Complete assignments of 1H and 13C NMR resonances are reported

Remarkable Brain Penetration of Cyclopentadienyl M(CO)₃⁺ (M = ^99mTc, Re) Derivatives of Benzothiazole and Benzimidazole Paves the Way for Their Application as Diagnostic, with Single-Photon-Emission Computed Tomography (SPECT), and Therapeutic Agents for Alzheimer’s Disease

The synthesis and evaluation of three novel 99mTc complexes (99mTc-1–3) and their corresponding Re complexes (Re-1–3), in which the phenyl ring of 2-phenylbenzothiazole or 2-phenylbenzimidazole is replaced by the cyclopentadienyl tricarbonyl [Cp99mTc­(CO)3] core, are reported. Both 99mTc and Re complexes were prepared from the corresponding ferrocenyl derivatives, and the Re complexes were fully characterized by elemental analysis, spectroscopic methods, and X-ray crystallography. The complexes exhibit effective in vitro binding to β-amyloid (Aβ) plaques and fibrils, inhibit Aβ fibril formation, and significantly reduce Aβ-induced cytotoxicity and reactive oxygen species production in neuronal cell cultures. The brain uptake of the 99mTc complexes ranges between 7.94 and 3.99% ID/g at 2 min p.i., being the highest recorded for potential 99mTc Aβ plaque imaging probes in mice. Powered by their high brain uptake, the complexes represent strong theranostic candidates against Alzheimer’s disease combining single-photon-emission computed tomography diagnostic (99mTc complexes) and antiamyloid therapeutic (Re complexes) potential

Effective Labeling of Amine Pharmacophores through the Employment of 2,3-Pyrazinedicarboxylic Anhydride and the Generation of <i>fac-</i>[M(CO)₃(PyA)P] and <i>cis–trans</i>-[M(CO)₂(PyA)P₂] Complexes (PyA = Pyrazine-2-carboxylate, P = Phosphine, M = Re, ^99mTc)

The fac-[M­(CO)3(PyA)­(P)] and cis–trans-[M­(CO)2(PyA)­(P)2] neutral complexes (M is Re or 99mTc), based on the mixed ligand strategy with pyrazine-2-carboxylic acid (PyAH) as the bidentate N,O and triphenylphosphine as the monodentate P ligand, are presented. Through the employment of the anhydride of pyrazine-2,3-dicarboxylic acid (PyDA), the PyAH scaffold was conveniently derivatized with the model bioactive amine 1-(2-methoxyphenyl)­piperazine, the active part of the 5-HT1A antagonist WAY100635. Reaction of either PyAH or the pharmacophore-bearing PyAH ligand (L1H) with fac-[M­(CO)3]+ core in water yielded the intermediate fac-[M­(CO)3(PyA)­(H2O)] complexes. The labile aqua ligand was easily replaced by PPh3 to yield the fac-[Re­(CO)3(PyA)­(PPh3)] complexes, while in toluene under reflux, the cis–trans-[Re­(CO)2(PyA)­(PPh3)2] complexes were obtained. The latter complexes were alternatively obtained from mer-[Re­(CO)3(PPh3)2Cl] by refluxing with the PyA ligand in toluene. The analogous 99mTc complexes were synthesized quantitatively, showing excellent stability in competition studies. The methodology described herein represents a practical procedure for the effective integration of the fac-[M­(CO)3]+ core with amine-bearing biologically active compounds for diagnosis/therapy

Dicarbonyl <i>cis</i>-[M(CO)₂(N,O)(C)(P)] (M = Re, ^99mTc) Complexes with a New [2 + 1 + 1] Donor Atom Combination

The synthesis and characterization of the dicarbonyl mixed ligand <i>cis</i>-[Re­(CO)₂(quin)­(cisc)­(PPh₃)] complex, <b>4</b>, where quin is the deprotonated quinaldic acid, cisc is cyclohexyl isocyanide, and PPh₃ is triphenylphosphine, is presented. The synthesis of <b>4</b> proceeds in three steps. In the first, the intermediate <i>fac</i>-[Re­(CO)₃­(quin)­(H₂O)] aqua complex <b>2</b> is generated from the <i>fac</i>-[NEt₄]₂­[Re­(CO)₃Br₃] precursor, together with the brominated products <i>fac</i>-[Re­(CO)₃­(quinH)­(Br)] <b>1a</b> and <i>fac</i>-[NEt₄]­[Re­(CO)₃(quin)­(Br)] <b>1b</b>, in low yield. In the following step, replacement of the aqua ligand of complex <b>2</b> by the monodentate isocyanide ligand leads to the formation of <i>fac</i>-[Re­(CO)₃­(quin)­(cisc)], <b>3</b>. In the third step replacement of the species <i>trans</i> to the isocyanide carbonyl group of <b>3</b> by a phosphine generates complex <b>4</b>. The Re complexes <b>2</b>–<b>4</b> were prepared in high yield and fully characterized by elemental analysis, spectroscopic methods, and X-ray crystallography. At the technetium-99m (^99mTc) tracer level, the analogous complexes <b>3′</b> and <b>4′</b> were produced in high radiochemical purity, characterized by comparative reverse phase high-performance liquid chromatography and showed high resistance to transchelation by histidine or cysteine. This new [N,O]­[C]­[P] donor atom combination with the <i>cis</i>-[M­(CO)₂]⁺ core (M = Re, ^99mTc) is a promising scaffold for the development of novel diagnostic and therapeutic targeted radiopharmaceuticals