Adriano Duatti

A new efficient method for the preparation of 99mTc-radiopharmaceuticals containing the TcN multiple bond

An improved method for the preparation of 99mTc-radiopharmaceuticals containing the TcN multiple bond, in sterile and apyrogen conditions, is described. This method is based on the reaction of [99mTc]pertechnetate with ligands derived from S-methyl dithiocarbazate [H2NN(R)C(S)SCH3 [R = H, CH3], in the presence of HCl and tertiary phosphines. It was found that these derivatives can behave both as sources of nitride nitrogen ions (N3−) and as coordinating ligands. The reaction leads to the formation of intermediate technetium-nitrido complexes in high yield. These intermediate species can be used as suitable prereduced substrates for the preparation of technetium-nitrido radiopharmaceuticals through simple substitution reactions with appropriate exchanging ligands.

Clearance of technetium 99m N-NOET in normal, ischemic-reperfused, and membrane-disrupted myocardium

BackgroundTechnetium 99m-labeled bis (N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium(v) (99mTcN-NOET) is a new neutral cardiac perfusion imaging agent that has been shown to have very high uptake and retention in vitro. The purpose of this study was to determine the clearance kinetics of 99m TcN-NOET in control, ischemic-reperfused, and membrane-disrupted myocardium.Methods and ResultsAfter a 100 μCi (3.7×106 Bq) bolus of 99mTcN-NOET was injected, myocardial clearance was monitored for 1 hour by the use of a sodium iodide detector in 30 isolated, Krebs-Henseleit (KH) perfused rat hearts. Seven hearts were used as controls (group 1). In seven ischemic-reperfused hearts, tracer administration and uptake was followed by 30 minutes of no flow and 1 hour of reflow (group 2). In six additional ischemic-reperfused hearts, tracer administration was followed by deprivation of flow for 1 hour followed by 1 hour of reflow (group 3). Six hearts were perfused with a 0.5% Triton X-100 KH perfusate for 1 hour (group 4). Four hearts were perfused with KH for 10 minutes, followed by cyanide for 10 minutes (group 5). This cycle was repeated three times. Activities remaining in each heart at the end of each experiment were quantitated, and activity at peak uptake was calculated. The 99mTcN-NOET myocardial clearance was near linear in the control (0.6±0.4) and both ischemic-reperfused groups with virtually no fractional clearance (1.2%±0.6% and 2.1%±0.6%, respectively; p=NS). In the Triton X-100 membrane-disrupted hearts, clearance was substantial (94.2%±4.0%; p<0.0001 compared with the control and ischemic-reperfused groups). Cyanide treatment produced rapid clearance, which was arrested by a return to the standard KH perfusate. Peak uptake as a percentage of injected dose was 74.9%±1.4% for all groups combined.ConclusionThus 99mTcN-NOET has extremely high myocardial retention after 1 hour in normal myocardium and is not significantly affected by ongoing myocardial ischemia or reperfusion injury in this model. Clearance is increased markedly in extreme conditions of membrane disruption. These data are consistent with the concept that 99mTc-NOET is localized predominantly in or on cell membranes. 99mTcN-NOET is a promising, new myocardial perfusion imaging agent that exhibits a stable myocardial distribution in the setting of acute developing injury.

Synthesis and characterization of new technetium(I) and rhenium(I) Schiff base complexes. Crystal structure of [M(PPh3)2(CO)2 {(C3H2NS)NCHC6H4O}] (MTc, Re; C3H2NSThiazol-2-yl)

Abstract [M(PPh3)2(CO)3Cl] (M  Tc, Re) reacts with the lithium salt of the Schiff base N-orthohydroxybenzylidene-2-thiazolylimine in boiling THF to yield [M(PPh3)2(CO)2 {(C3H2NS)NCHC6H4O} ]. The structure of the two isomorphous complexes has been determined by X-ray crystallography based on single- crystal diffractometer data and refined to the final R factor of 0.039 for the Re complex and 0.059 for the Tc complex. The compounds are monoclinic, space group P21/n, with Z=4. Crystal data are: [Re- (PPh3)2(CO)2(L)] (L=Schiff base ligand),a=17.875(5), b=24.948(4), c=9.279(5) A, β=102.39(3)°; [Tc(PPh3)2(CO)2(L)], a=17.905(5), b=24.895(4), c=9.285(6) ) A, β=102.63(3)°. The metal ions are six-coordinate distorted octahedral, with trans PPh3, cis CO groups, and one chelate bidentate anion. Structural details compare very favourably in the two complexes. Selected bond lengths are: ReP (mean) 2.44, ReC (mean) 1.89, ReO 2.157(5), ReN 2.211(6); TcP (mean) 2.44, TcC (mean) 1.89, TcO 2.164(5), TcN 2.210(7) A.

Synthesis and biodistribution of nitrido technetium-99m radiopharmaceuticals with dithiophosphinate ligands: a class of brain imaging agents

The symmetrical complexes [99mTc][TcN(R2PS2)2] [R = CH3, CH2CH3, CH2CH2CH3, CH2(CH3)2], and the unsymmetrical complex [99mTc][TcN(Me2PS2)(Et2PS2)] have been prepared, at tracer level, through a two-step procedure involving the preliminary formation of a prereduced technetium nitrido intermediate followed by substitution reaction onto this species by the appropriate dithiophosphinate ligand [R2PS2]Na. The chemical identity of the resulting complexes have been established by comparison with the corresponding 99Tc-analogs prepared, at macroscopic level, by reacting the complex [99TcNCl4] [n-Bu4N] (n-Bu = n-butyl) with an excess of ligand in methanol, and characterized by elemental analyses and spectroscopic techniques. The complexes are neutral and lipophilic, and possess a square pyramidal geometry, with an apical Tc identical to N group and two dithiophosphinate ligands spanning the four positions on the basal plane through the four sulfur atoms of the > PS2 group. In vitro studies showed that these radiopharmaceuticals are stable in solution and that their chemical identity was not altered after incubation with rat blood. Biodistribution studies have been carried out in rats and primates. The results demonstrate that these compounds are significantly retained into the brain of these animals for a prolonged time. Planar gamma camera images have been obtained in monkeys showing a good visualization of the cerebral region. However, the existence of persistent blood activity yields a brain/blood ratio lower than that observed with other 99mTc-based brain perfusion imaging agents.

Tc(IV)Cl4(PPh3)2 and Tc(III)Cl3(CH3CN)(PPh3)2 as precursors of trans dioxo technetium(V) complexes with chelating amines and tetraazamacrocycles

Abstract The trans dioxo complexes [TcO2(L)]+ (L = 1,4,8,11-tetraazacyclotetradecane (cyclam), 1,4,8,11-tetraazacyclotetradecane-5-one, 1,4,8,11-tetraazacyclotetradecane-5,7-dione) have been prepared through a new alternative route involving the reaction of excess of the appropriate ligand with the complexes [TcCl4(PPh3)2] and [TcCl3(CH3CN)(PPh3)2] in CH3CN solution, at room temperature. The yields of formation of the final products obtained through this new synthetic method (30–55%) are significantly higher than that found in the synthesis of the complex [TcO2(cyclam)]+ (7%) obtained through a previously reported procedure involving pertechnetate reduction by Na2S2O3 in alkaline solution and in the presence of the ligand or by substitution reaction onto the mono-oxo complex [TcOCl4]−. The new synthetic method was also efficiently applied to the synthesis of the trans dioxo complexes [TcO2(L′)2]+ (L = enthylenediamine, 1,3-propanediamine) and [Tc2(tad)]+ (tad = 1,5,8,12-tetraazadodecane), containing bidentate and tetradentate chelating amines, giving final yields similar to those obtained using [TcOCl4]− as starting substrate. These results indicate that the complex [TcCl4(PPh3)2] and [TcCl3(CH3CN)(PPh3)2] are superior precursors for the synthesis, at macroscopic level, of trans dioxo Tc(V) complexes with tetraazamacrocylic ligands as compared to [TcO4]− and [TcOCl4]−. All the complexes have been characterized by elemental analysis, FTIR and mass spectra, and magnetic susceptibility measurements in solution.

Labeling and biodistribution studies of Tc-99m radiopharmaceuticals with (o- hydroxyphenyl) diphenylphosphine

New Tc-99m radiopharmaceuticals with the ligand (o-hydroxyphenyl)diphenylphosphine have been prepared and their biodistributions evaluated in rats. The monoxo Tc(V) complex [99mTc(O)Cl(PO)2], the Tc(IV) complex [99mTc(OH)2(PO)2], the Tc(III) complex [99mTc(PO)3], and the nitrido Tc(V) complex [99mTc(N)(PO)2] have been characterized by TLC and HPLC chromatography, and their chemical structure elucidated by comparison with the corresponding complexes obtained using the beta-emitting isotope Tc-99g. Biodistribution studies of these complexes have been carried out in rats.

Design and synthesis of a redox-active tc-99m radiopharmaceutical with ferrocenedithiocarboxylate [FcCS = Fe(C5H4CS2)(C5H5)−]

The synthesis, at tracer level, of two Tc-99m complexes having the same chemical composition and structure, but differing by one electron in the total electron counting, is reported. These compounds have been prepared by reacting [99mTcO4]- with the piperidinium salt of the ligand ferrocenedithiocarboxylate {[Fe(II)(C5H4CS2)(C5H5)]- = FcCS}, in the presence of N-methyl S-methyldithiocarbazate as donor of N3-groups, and triphenylphosphine or SnCl2 as reducing agents. The formation of the neutral complex [99mTc(N)(FcCS)2] (compound A) and of the monocationic, mixed-valence complex [99mTc(N)(FcCS) (FcCS)]+ (compound B) {FcCS = [Fe(III)(C5H4CS2)(C5H5)]} was obtained in high yield. Both complexes comprise a terminal Tc triple bond N multiple bond and two FcCS ligands coordinated to the metal center through the two sulfur atoms of the -CS2 group, but they differ in the oxidation state of one of the two iron atoms of the coordinated FcCS ligands. In complex A, the two Fe atoms are both in the +2 oxidation state, while in B, one Fe atom is in the +2 and the other is in the +3 oxidation state. Thus, B is a mixed-valence Fe(II)-Fe(III) complex. B is easily converted into A by one-electron exchange with various reductants such as triphenylphosphine and excess SnCl2. Biodistribution studies in rats showed that complexes A and B are mostly retained in lungs and liver without any significant uptake in organs such as heart and brain.

Technetium-99m nitride radiopharmaceuticals

Following the introduction of an efficient method for the preparation of technetium-99m complexes containing a terminal Tc-N multiple bond, under conditions suitable for nuclear medicine applications, new radiopharmaceuticals for heart and brain imaging have been discovered. These compounds belong to the class of bi-substituted, square-pyramidal nitride TcV complexes with dithiocarbamate ligands, and are the first examples of radiopharmaceuticals of this type exhibiting interesting biological properties. The peculiar chemical characteristics of the Tc-N core can also be conveniently utilized for the design of radiopharmaceuticals incorporating bioactive peptides and having definite structural features.