99mTc-MAEC complexes: new renal radiopharmaceuticals combining characteristics of (99m)Tc-MAG3 and (99m)Tc-EC.

UNLABELLED: 99mTc-Mercaptoacetyltriglycine ((99m)Tc-MAG3) and (99m)Tc-L,L-ethylenedicysteine ((99m)Tc-LL-EC) are useful renal radiopharmaceuticals; however, both agents have renal clearances less than that of (131)I-orthoiodohippurate ((131)I-OIH), and (99m)Tc-LL-EC exists in dianionic and monoanionic forms at physiologic pH. In an effort to develop a superior (99m)Tc agent with a rapid clearance comparable with that of (131)I-OIH, we have designed a new ligand system, mercaptoacetamide-ethylene-cysteine (MAEC), which combines important structural features of both MAG3 and EC. METHODS: Biodistribution and clearance studies were performed on Sprague-Dawley rats using syn- and anti-(99m)Tc-L- and -D-MAEC coinjected with (131)I-OIH. Studies were also performed by coinjecting each isomer ( approximately 74 MBq [ approximately 2 mCi]) and 7.4-11.1 MBq (200-300 micro Ci) of (131)I-OIH in 3 volunteers with dual-isotope imaging performed using a camera system fitted with a high-energy collimator. Blood samples were obtained from 3 to 90 min after injection and urine samples were obtained at 30, 90, and 180 min. RESULTS: In the rats, <10% of the injected dose remained in the blood at 10 min after injection for all isomers, and the urine dose at 60 min ranged from 84% to 99% that of (131)I-OIH. The clearances of syn- and anti-(99m)Tc-L-MAEC in the rats were higher than the clearances for the D-isomers (P

New N(3)S donor ligand small peptide analogues of the N-mercaptoacetyl-glycylglycylglycine ligand in the clinically used Tc-99m renal imaging agent: evidence for unusual amide oxygen coordination by two new ligands.

Three new X-ray structurally characterized Re(V)O complexes, ReO(MEG(3)H(2)) (10), ReClO(MAEG(2)H(3)) (11), and [ReO(MECG(2)H(2))](2) (12), were prepared from protected forms of three new ligands, mercaptoethyl-glycylglycylglycine (MEG(3)H(5)), mercaptoacetamide-ethyl-glycylglycine (MAEG(2)H(5)), and mercaptoethyl-carbamoylmethyl-glycylglycine (MECG(2)H(5)). (Subscript on H indicates the number of dissociable protons.) Mercaptoacetyltriglycine (MAG(3)H(5)) is the ligand precursor for the clinically used Tc-99m renal imaging agent. The new potentially N(3)S donor ligands have a glycylglycine carboxyl end as in MAG(3)H(5), but a secondary amine (sp(3) N) replaces one amide (sp(2) N) of MAG(3)H(5). ReO(MEG(3)H(2)) (10) is a typical five-coordinate pseudo-square-pyramidal complex with the oxo ligand at the apex and the trianionic form of MEG(3)H(5) coordinated in the basal plane via N(3)S. In the other complexes, the quadridentate ligand has N(2)OS ligation, with the carbonyl oxygen of the glycyl amide group coordinated trans to the oxo ligand. This unusual ligation mode, which is facilitated by the preferred endo configuration of the ligated glycyl sp(3) N, leaves a vacant basal coordination site. In 11, the chloro ligand completes the equatorial plane, whereas, in 12, a glycine carboxylate oxygen of the ligand on the partner Re completes the equatorial plane. Both complexes thus possess an unexpected pseudo-octahedral geometry. For 10, 11, and 12, the (1)H NMR spectra, monitored from high to low pH, exhibited changes only when the pH was lowered below 6. This finding indicates that at physiological pH these complexes possess the desirable characteristic of existing as one monomeric species having only one ionization state, with the coordinated sp(3) N deprotonated. Below pH 6 and above pH approximately 4, changes in the (1)H NMR shifts indicate that this sp(3) N has become protonated. Thus, the N(3)S ligands in all three complexes exhibit normal coordination above pH approximately 4. However, X-ray data for 11 and 12 and some NMR evidence for 11 indicate that the ligands of the two complexes rearrange at low pH (<3). The striking differences between the solution- and solid-state structures reinforce the caveat that solution structural studies conducted at physiological pH are necessary in order to gain insight into the nature of radiopharmaceuticals.

Re(V)=O(N(2)S(2)) Complexes with N(2)S(2) = Thio-Amido-Secondary Amine-Thio Chelate Ligands: Synthesis, Structure, and Characterization of Solution Forms.

Anti- and syn-ReO(L-cysteine-acetyl-cysteamine) (1 and 2, respectively), and the dimethyl derivatives anti- and syn-ReO(L-penicillamine-acetyl-cysteamine) (3 and 4, respectively), were synthesized. Anti and syn refer to the relationship of the oxo ligand and carboxyl group of the cysteine/penicillamine residue. In the structures of 1 and 4, determined by X-ray diffraction, the oxo/carboxyl relationship was anti in 1 and syn in 4. Such thio-amido-amine-thio (MAMA for monoamido monoamine) type complexes are being investigated as radiopharmaceuticals. The charge and the number of species present under physiological conditions influence biodistribution, and understanding factors influencing the pK(a) of the coordinated secondary amine is essential for successful design of such agents. Dissociation of the proton on the secondary amine alters the charge and structure. For both 1 and 2, the (1)H NMR spectra, monitored as a function of pH, exhibited changes in two pH regions: near pH 4 the signals (especially the H(alpha) of the cysteine residue) shifted, and from pH approximately 6-8 the signals shifted again and broadened. These shift changes are consistent with dissociation of the carboxyl proton to give a monoanion I, and of the amine proton to give a dianion II, respectively. The cysteamine chelate ring of 1 and 4, anchored by the amine donor, is highly puckered in the solid state. Torsion angles, calculated from (1)H NMR (3)J values at pH 3, 5 and 8, indicate that in solution the cysteamine chelate ring is also highly puckered in the neutral form and I, but relatively planar in II. Since five-membered chelate rings are more planar when an anchoring amine is deprotonated, the data are consistent with II being an NH-deprotonated form rather than an OH(-) axially ligated form. The high acidity of the amine in 1 and 2 compared to analogues with two amine donors indicates that the amido group is a modest donor. The signal broadening observed as I and II interconvert, an unusual effect for NH/N(-) exchange, is due primarily to the low rate of exchange at the OH(-) concentration needed to convert I to II. Making the metal (Re/Tc) more electron rich may decrease the acidity of the NH, but since the NH in 1 and 2 is particularly acidic, this approach is unlikely to work. Our results suggest that introduction of an electron-withdrawing group into the ligand may lower the NH pK(a) of the complex below the physiologically relevant range and give a species with a well-defined charge.

Rhenium(V) Oxo Complexes of Novel N(2)S(2) Dithiourea (DTU) Chelate Ligands: Synthesis and Structural Characterization.

The compounds RNHC(=S)NH(CH(2))(n)()NHC(=S)NHR were prepared in a search for new, relatively small N(2)S(2) ligands. These dithiourea (DTU) ligands are the first chelates containing two potentially bidentate thiourea moieties. A one-step reaction of 1,3-diaminopropane (1) with aryl or alkyl isothiocyanates or of 1,2-diaminoethane (2) with phenyl isothiocyanate afforded the target ligands in excellent yields (95-98%). The Re(V)=O complexes of RNHC(=S)NH(CH(2))(3)NHC(=S)NHR ligands were obtained through ligand exchange reactions with Re(V) precursors. The chemistry required neither protection of the sulfur atoms for ligand synthesis nor deprotection prior to metal complexation. The structure of (1-phenyl-3-(3-phenylthioureido)propyl]thioureato)oxorhenium(V) (7a), determined by X-ray diffraction methods, revealed the expected pseudo-square-pyramidal geometry with an N(2)S(2) basal and an apical oxo donor set. Both coordinated N's (N(c)) were deprotonated. One uncoordinated N (N(u)) was deprotonated, producing a neutral complex containing an unexpected new type of dianionic, four-membered N,S chelate. In the crystal, the N(u) atoms, N(3)H and N(4), of one complex each formed an H-bond with N(4) and N(3)H, respectively, of a symmetry-related complex. The N(c)-C-S bond angles (106.1(6) and 101.5(6) degrees ) were severely distorted from the 120 degrees expected for an sp(2)-hybridized C. However, these small bite angles and the large N-Re-N bond angle (86.1(3) degrees ) allowed for the formation of two four-membered chelate rings with normal Re-N and Re-S bond distances. Attempts to prepare complexes with the PhNHC(=S)NH(CH(2))(2)NHC(=S)NHPh ligand were unsuccessful. These results suggest that a central five-membered chelate ring is too small to accommodate bidentate coordination of both thiourea moieties. NMR studies in methanol established that the neutral complex with one uncoordinated N deprotonated was the favored form in neutral and basic solutions. However, under acidic conditions, a cationic form with both uncoordinated N's protonated was favored.

Synthesis and Characterization of Rhenium(V) Oxo Complexes with a New Thiol-Amide-Thiourea Ligand System. X-ray Crystal Structure of [1-Phenyl-3-[2-((2-thioacetyl)amino)ethyl]thioureato]oxorhenium(V).

General methods for preparing Re(V)O complexes with a novel series of thiol-amide-thiourea (TATU) ligands, a new class of N(2)S(2) chelates, were developed. The TATU ligands, the first multidentate systems designed with a bidentate thiourea moiety, have been used to prepare the first high-valent transition metal complexes with bidentate thiourea coordination. Direct reaction of N-(2-aminoethyl)-2-((triphenylmethyl)thio)acetamide (1) with phenyl, 4-methoxyphenyl, 4-chlorophenyl, and methyl isothiocyanate afforded ready access to the corresponding S-protected TATU ligands in one step. A two-step preparation of the N,N-dimethylthiourea TATU ligand derived from 1 was also developed. Deprotection of thiols in trifluoroacetic acid with triethylsilane followed by a ligand exchange reaction with Re(V)O precursors yielded neutral ReO(TATU) complexes. The structure of [1-phenyl-3-[2-((2-thioacetyl)amino)ethyl]thioureato]oxorhenium(V) (6a) was determined by X-ray diffraction methods. Crystal data for 6a: C(11)H(12)N(3)O(2)ReS(2), fw 468.6, orthorhombic, Pca2(1); a = 22.605(5) Å, b = 13.029(3) Å, c= 9.698(2) Å; V = 2856.3(11) Å(3); Z = 8. The coordination environment of 6a was pseudo-square-pyramidal with a deprotonated thiol S, deprotonated amide N, deprotonated thiourea N, and thiocarbonyl S coordinated in the basal plane and the oxo ligand in the apical position. The thiourea function forms a four-membered chelate ring in the multidentate TATU ligands. The two N-C and the S-C bond distances within the monodeprotonated thiourea moiety were typical of bonds with multiple-bond character. Solution (1)H NMR data for all five complexes were consistent with the solid-state structure of 6a. A broad singlet attributable to the uncoordinated NH group of thiourea was observed for the monosubstituted thiourea complexes but was not present for the N,N-dimethylthiourea derivative. Instead, two singlets of equal intensity were observed for the two methyl groups, indicating that there is restricted rotation around the C-N(CH(3))(2) bond and an extended pi system in the thiourea moiety. The four-membered ring might cause difficulty because the M-S distance would be relatively long in an undistorted ligand. This may be the reason such chelate ligands have not been previously investigated. However, the N-C-S angle narrows to approximately 105 degrees, permitting a Re-S bond with a typical bond length to be formed. We conclude that such a ring represents a versatile new building block to create multidentate ligands.