Prahlad R. Singh

In vitro and in vivo characterization of a 99mTc complex with tris(hydroxymethyl)phosphine (THP)

The water-soluble, monophosphine ligand tris(hydroxymethyl)phosphine (THMP) was complexed with 99mTc. The 99mTc-THMP was formed in high radiochemical purity by simply mixing 99mTcO4- with THMP over a wide pH range. In vitro and in vivo studies indicated the complex to be highly stable under the respective conditions. HPLC analysis indicated a singular species with a retention time identical to the known [ReO2(THMP)4]1 complex. Results show that the hydroxymethylphosphine functionality is attractive for use in designing new 99mTc radiopharmaceuticals.

Transition-metal chemistry of main-group hydrazides. Part 2. A new oxime thiosemicarbazide framework as a novel SN multifunctional tripodal ligand for palladium(II): synthetic and X-ray crystal structural investigations

Thiosemicarbazide reacted with butane-2,3-dione oxime to give a Schiff-base product HL via the selective reaction of the hydrazine nitrogen atom. The ligating properties of this new oxime thiosemicarbazide ligand L with palladium(II) were investigated and in the complex [PdL(Cl)] 1 the palladium(II) atom is bound in a trimodal, cis arrangement to the oxime nitrogen, hydrazine nitrogen and the sulfur centre. The crystal structure of complex 1 further reveals that the oxime thiosemicarbazide HL has reacted with [PdCl2(PhCN)2] presumably via the elimination of HCl, in the thiol rather than the thione form. The hydrogen-bonding interaction of the oxime hydrogen that caused HL to be a dimer in the solid state is lost upon complexation with palladium(II), giving complex 1 a monomeric structure. X-Ray crystal data; for HL, monoclinic, space group P21/c, a= 11.082(4), b= 12.679(2), c= 6.101(2)A, Z= 4, R= 0.044 and R′= 0.064; 1, triclinic, space group P, a= 7.660(3), b= 12.972(5), c= 22.325(8)A, α= 89.26(3), β= 81.53(3), γ= 84.75(3)°, Z= 8, R= 0.045 and R′= 0.064.

Transition metal chemistry of main group hydrazides, part 14: Evaluation of new Tc-99m chelates of thiol functionalized phosphorus hydrazides

Ligands containing a combination of amine or amide nitrogens and thiol functionalities have been found to form stable chelates with Tc-99m, presumably in oxidation state +5. Two new thio-phosphorus monohydrazides [(MeO)2P(S)NMeNHCH2C6H4SH], SL1 and [(MeO)2P(S)NMeNHC(O)C6H4SH], SL2 were synthesized and their complexation properties with Re(V) and Tc-99m have been studied. Neutral-lipophilic Tc-99m chelates with both SL1 and SL2 were formed in high yields (95-97%) as a single species ascertained by electrophoresis and reversed-phase HPLC. Biodistribution studies show good in vivo stability and primary clearance of both 99mTc chelates is via the hepatobiliary pathway. Re(V) complexes with SL1 and SL2 were also synthesized using the ReOCl3(PPh3)2 precursor to obtain the product ReOCl(L)(PPh3), where L = SL1 or SL2. H+ was lost from the N-atom and the thiol group in these Re chelates. Even though the Tc-99m chelates of SL1 and SL2 formed at tracer levels are not identical to the Re-chelates (different synthons were used), the Re data suggests complexation of Tc-99m by these hydrazido-thiol ligands will be similar to N,S ligand systems previously used. The good in vitro and in vivo stability and high yields of the Tc-99m complexes of SL1 and SL2 indicate the potential hydrazido-thiols hold for use as a basis in formulating new Tc-99m radiopharmaceuticals, particularly when thiol moieties are used in conjunction with multi-functional phosphorous hydrazide compounds.

Synthesis and characterization of a neutral and lipophilic Ph3PN99mTcO3 complex

Abstract Ph3PNSiMe3 reacts with 99mTcO4− to form an ion pair that in soluble in organic solvents. Heating of the ion pair produces a new 99mTc species that is neutral and lipophilic and stable in dry toluene for ⩾ 2 h. Dissolving this new complex in 1:1, EtOH:H2O results in conversion of the product back to the ion pair which will limit its in vitro and in vivo stability. The chromatographic properties of the ion pair and the 99mTc species produced when heated in toluene are similar to the analogous Re complexes with Ph3PNSiMe3 which should have the following respective structures: [Ph3PNH2+][99mTcO4−] and Ph3PN99mTcO3. These results indicate the potential of phosphinimine ligands in formulation of new 99mTc radiopharmaceuticals, particularl if phosphinimine ligand derivatives are developed that provide substantially improved stability of the respective complexes in aqueous solutions.

Synthesis, characterization and biodistribution studies of a neutral-lipophilic Tc-99m N3S2 chelate

Diaminedithiols (DADT) are known to form neutral-lipophilic complexes with 99mTc in aqueous solutions, where they are readily formed in high yields and demonstrate excellent stability. A new triaminedithiol (TADT) ligand was synthesized, characterized and shown to form a neutral-lipophilic 99mTc-chelate. The biodistribution of this 99mTc chelate in rats showed that its uptake in brain or heart following i.v. injection of the 99mTc chelate was low, but activity taken up was retained over a long period of time. The in vivo and in vitro properties of this chelate indicate the possibility that chemical modification of this TADT ligand may produce ligand systems that form 99mTc chelates with suitable diagnostic properties.

New Directions in the Development of Water-Soluble Phosphines and Transition Metal Compounds

Abstract The water-soluble bisphosphines, 1,2-bis(bis(hydroxymethyl)phosphino)benzene (“HMPB”) (1) and 1,2-bis(bis(hydroxymethyl)phosphino)ethane (“HMPE”) (2) were synthesized in near quantitative yields by the catalytic hydroformylation of H2PC6H4PH2 and H2PCH2CH2PH2 in the presence of formaldehyde in aqueous media.1.2 The reactions of these chelating bisphosphines 1 and 2 with Pt(COD)Cl2 and Pd(PhCN)2Cl2 produced water-soluble Pt(II) and Pd(II) complexes M[(HOH2C)2PC6H4P(CH2OH)2]2Cl2 (M = Pt, 3; Pd, 4) and M[(HOH2C)2PCH2CH2P(CH2OH)2]2Cl2 (M = Pt, 5; Pd, 6) respectively. The reactions of 1 and 2 with Re(O2)I(Ph3)2 and Re(O)2(NHC5H5)4]Cl to produce new water-soluble Re(V) complexes are also described. All the new compounds were characterized by 1H and 31P NMR spectroscopy. X-ray structures of representative Pd(II) and Re(V) complexes as shown below confirmed the chemical constitution of this new generation of water-soluble metal complexes.

A new 99mTc-complex with a germanium-hydrazide (GeTH) ligand

A new tetrahydrazido-germanium (GeTH) ligand was synthesized, characterized and complexed with 99mTc. The negatively charged 99mTc-chelate was shown to form in high yields at neutral pH in the absence of other reducing agents and exhibits high in vitro and in vivo stability.

Reaction of methylhydrazine with dimethyl chlorothiophosphate

The reaction of 2 equivalents of methylhydrazine with 1 equivalent of (MeO)2P(S)Cl at 0 °C produced the phosphorus hydrazide (MeO)2P(S)NMeNH21 in good yield. However, at 25 °C a mixture of three products was obtained according to 1H and 31P NMR spectra. The pure individual components were separated by column chromatography. Proton and 31P NMR analysis revealed them to be 1, (MeO)2P(S)(NMeNH)(S)P(OMe)22 and (MeO)2P(S)NHNHMe 3. During the chromatographic separation of 1–3 another component was also eluted in 5–8% yield, 1H, 31P NMR and FAB mass spectrometric analysis of which indicated it to be (MeO)2P(S)(NMeNH)(O)P(OMe)Me4. New synthetic strategies to produce 2 in good yields are also described.

Organometallic phosphinimines as building blocks for potential new radiopharmaceuticals. Synthesis, structure and reactivity of Ph3P=NH2+ReO4-

Reactions of the organometallic phosphinimine Ph3P=N-SiMe3 (1), with aqueous ReO4- and 188ReO4- yield the ion pairs Ph3P=NH2+MO4- (M=Re (2); 188Re (4)). The ion pairs undergo dehydration upon heating to produce the neutral Re(VII) species: Ph3P=N-MO3 (M=Re (3); 188Re (5)). The solid state structure of Ph3P=NH2+ReO4- (2) shows the presence of hydrogen bonding between the iminato hydrogen and the rhenium oxo center. The relevance of such reactions for the design of new radiopharmaceuticals is discussed

The Potential of Phosphinimines as Building Blocks for a New Generation of Radiopharmaceuticals

Abstract Reaction of Ph3P[dbnd]NSiMe3 with NH4ReO4 produced the ion pair Ph3P[dbnd]NH2 +ReO4- which was characterized by spectroscopic data and X-ray crystallography. The thermolysis of this ion pair gave the neutral Re(VII) complex: Ph3P[dbnd]N-ReO3 in good yields. The reactions of 99mTcO4- or 188ReO4- with Ph3P[dbnd]N-SiMe3 also produced the metallic radioisotope analogues of the ion pair: Ph3P[dbnd]NH2+MO4- (M = 99mTc or 188Re) which on heating produce the neutral species Ph3P[dbnd]N-MO3 (M = 99mTc or 188Re). The implications of such small molecule 99mTc or 188Re complexes for the development of a new genre of radiopharmaceuticals will be discussed.