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The reaction of an aminopolycarboxylate ligand, aspartic- N-monoacetic acid (ASMA), with [Re(CO)3(H2O)3]+ was examined. The tridentate coordination of ASMA to this ReI(CO)3 precursor yielded fac-Re(CO)3(ASMA) as a mixture of diastereomers. The chemistry is analogous to that of the TcI(CO)3 complex, which yields fac-99mTc(CO)3(ASMA) under similar conditions. The formation, structure, and isomerization of fac-Re(CO)3(ASMA) products were characterized by HPLC, 1H NMR spectroscopy, and X-ray crystallography. The two major fac-Re(CO)3(ASMA) diastereomeric products each have a linear ONO coordination mode with two adjacent five-membered chelate rings, but they differ in the endo or exo orientation of the uncoordinated acetate group, in agreement with expectations based on previous studies. Conditions have been identified for the expedient isomerization of fac-Re(CO)3(ASMA) to a mixture consisting primarily of one major product. Because different isomeric species typically have different pharmacokinetic characteristics, these conditions may prove useful for the practical isolation of a single 99mTc(CO)3(ASMA) species, thus allowing the isolation of the isomer that has optimal imaging and pharmacokinetic characteristics. This information will aid in the design of future 99mTc radiopharmaceuticals. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Aminocarboxyphosphonates chelate tridentately to fac -[99mTc/Re(CO) 3 ]+ cores. • X-ray/NMR/HPLC data unambiguously establish phosphonate binding to the cores. • Some chelates form linkage isomers that interconvert in a pH-dependent ratio. • Isomers with phosphonate binding are favored over carboxylate binding at pH > 6. • Phosphonate-to- fac -[99mTc(CO) 3 ]+ binding is totally robust in in vivo rat studies. Abstract Ligands that coordinate via dianionic phosphonate groups have not been widely utilized in radiopharmaceuticals. N -(phosphonomethyl)iminodiacetic acid (1 , PMIDA) and N- (phosphonomethyl)glycine (2 , PMG) were investigated as new chelators for the 99mTc/Re-tricarbonyl "core" (fac -M(CO) 3 , M = 99mTc, Re) present in a major class of radiopharmaceuticals. fac -M(CO) 3 (PMIDA) and fac -M(CO) 3 (PMG) complexes were studied by HPLC and 1H/13C/31P NMR methods for M = Re (Re-1 and Re-2) and by HPLC for M = 99mTc (99mTc-1 and 99mTc-2). Re-1 and 99mTc-1 complexes exhibit a similar pH-dependent equilibrium between geometric linkage isomers (M-1a and M-1b). However, only one isomer exists for M-2 under all conditions. Structural characterization by X-ray crystallography reveals the presence of a bond between a phosphonate oxygen and the Re(I) center in fac -Re(CO) 3 (PMG) (Re-2). Detailed comparisons of NMR data for Re-2 conclusively demonstrate that the phosphonate group is coordinated in Re-1b (isomer favored at high pH) but not in Re-1a , which has a dangling N -(phosphonomethyl) group. To our knowledge, Re-1b and Re-2 and their 99mTc analogs are the first well-documented examples of complexes with these metal-tricarbonyl cores having a dianionic phosphonate group directly coordinated in a fac -M(CO) 3 -O-P grouping. Pharmacokinetic studies using Sprague-Dawley rats reveal that 99mTc-2 is a robust tracer. Hence, phosphonate groups should be considered in designing 99mTc and 186/188Re radiopharmaceuticals, including agents with bioactive moieties attached to dangling carboxylate or phosphonate groups. [ABSTRACT FROM AUTHOR]

We study Re analogues of 99mTc renal agents to interpret previous results at the 99mTc tracer level. The relalive propensities of amine donors versus carboxytate oxygen donors of four L = polyaminocarboxylate ligands to coordinate in fac-[Rel(CO)3L]n complexes were assessed by examining the reaction of fac.(Rel(CO)3(H2O)3]+ under conditions differing in acidity and temperature. All four L (N,N-bis.(2.aminoethyl)glycine (DTGH), N,N.ethylenediaminediacetic acid, diethylenetriarnine-N-malonic acid, and diethylenetriamine-Nacetic acidi can coordinate as tridentate ligands while creating a dangling chain terminated in a carboxyl group. Dangling carboxyl groups facilitate renal clearance in fac'[99mTcI(CO)3L]n agents. Under neutral conditions, the four ligands each gave two fac-[Rel(CO)3L]n products with HPLC traces correlating well with known traces of the fac-[99mTcl(CO)3L]n mixtures. Such mixtures are common in renal agents because the needed dangling carboxyl group can compete for a coordination site. However, the HPLC separations needed to assess the biodistribution of a single tracer are impracitcal in a clinical setting. One goal in investigating this Re chemistry is to identity conditions for avoiding this problem of mixtures in preparations of fac.[99mTcl(CO)3L]n renal tracers. After separation and isolation of the fac-[Rel(CO)3L]n products, NMR analysis of all products and single crystal X-ray crystallographic analysis of both DTGH products, as well as one product each from the other L, allowed us to establish coordination mode unambiguously. The product favored in acidic conditions has a dangling amine chain and more bound oxygen. The product favored in basic conditions has a dangling carboxyl chain and more bound nitrogen. At the elevated temperatures used for simulating tracer preparaiton, equilibration was facile (ca. 1 h or less), allowing selective formation of one product by utilizing acidic or basic conditions. The results of this fundamental study offer protocols and guidance useful for the design and preparation of fac.[99mTcl(CO)3L]n agents consisting of a single tracer. [ABSTRACT FROM AUTHOR]

Parallel studies of the preparation of Re and 99mTC agents aid in interpreting the nature of tracer 99mTC radiopharmaceuticals. Aqueous solutions of the fac-[99mTc(CO)3(H2O)3]+ cation are gaining wide use and are readily prepared, but such solutions of the fac-[Re(CO)3(H2O)3]+ cation (1) are not so easily accessible. Herein we describe a new, reliable, and straightforward preparation of aqueous solutions of 1, characterized by HPLC and ESI-MS. Treatment of solutions of 1 with thioether-bearing amino acids, AAH = S-methyl-L-cysteine (MECYSH), S-propyl-L-cysteine (PRCYSH), and methionine (METH), gave high yields of fac-Re(CO)3AA complexes. X-ray crystallographic and NMR analyses indicated that MECYS-, PRCYS-, and MET- were bound in fac-Re(CO)3AA complexes as tridentate monoanionic ligands through amino, thioether, and α-carboxyl groups. In CD3OD, ¹H NMR spectra have broad signals but have two sets of signals at −10 °C, consistent with two isomers with different configurations at the pyramidal sulfur; these interconvert slowly on the NMR time scale at low temperatures. Indeed, the crystal structure of the fac-Re(CO)3(PRCYS) reveals a mixture of the two possible diastereoisomers. S-(Carboxymethyl)-L-cysteine (CCMH2) and 1 gave two products, 5A (kinetically favored) and 5B (thermodynamically favored). X-ray crystallographic analyses of a crystal of 5B and of a 1:1 cocrystal of 5A and 5B showed that 5A and 5B are diastereoisomers with the CCMH- α-carboxyl group dangling. In addition to the amino and thioether groups, the S-(carboxymethyl) carboxyl group is coordinated, a feature that slows interconversion of diastereoisomers relative to the other fac-Re(CO)3AA complexes because interconversion can now occur only after the rupture of Re-ligand bonds. These N, O, and S tridentate adducts are quite stable, and the grouping has promise in 99m Tc(CO)3 tracer development. [ABSTRACT FROM AUTHOR]

Two new N2S2 ligands [S-trityl-l-cysteine-acetamide-ethanethiol ethyl ester (Tr-l-CAATH2-Et, 1) and S-trityl-d-penicillamine-acetamide-(2-methyl-2-propanethiol) ethyl ester (Tr-d-TMCAATH2-Et, 2)] were prepared. These ligands, with the electron-withdrawing carboxyl group separated by only two bonds from the NH amine group, belong to monoamide-monoamine-dithiol (MAMA) class of chelates that typically form M(V)O(N2S2) (M=Tc, Re) complexes with the ligand secondary amine pKa of ∼6–7 and both syn and anti isomers. Re(V)O(N2S2) complexes were prepared from 1 and 2 with the dangling ester either syn or anti to the Re&z.dbnd6;O intact or hydrolyzed; the latter, ReO(l-CAATH2) and ReO(d-TMCAATH2) have a carboxyl group needed for renal imaging when M=Tc. The gross structure of syn-ReO(l-CAATH-Et) (3) is typical of Re(V)O(N2S2) complexes. However, within the cys moiety of 3, an intramolecular H-bond between the ester carbonyl oxygen O(4) and the NH (N(2)⋯O(4) distance=2.80 A˚) causes the cys chelate ring to adopt an unusual conformation with the αC (C(5)) atom 0.42 A˚ below the plane defined by the cys S, Re, and N(2) atoms with respect to the Re&z.dbnd6;O group. From molecular mechanics (MM) analysis of ReO(l-CAATH2) models, the lowest-energy syn-ReO(l-CAATH2) structure has a corresponding region similar to that of the X-ray structure for 3, an N(2)H endo with respect to Re&z.dbnd6;O group, a N(2)H⋯O(4) hydrogen bond (2.69 A˚ N(2)⋯O(4) distance) contributing ∼5 kcal mol−1 to its stability and an αC atom deviating 0.24 A˚ from the cys S, Re, and N(2) plane. Computed structures with an exo N(2)H are ∼6 kcal mol−1 less stable than the lowest-energy endo analogue. Below pH ∼7, the 1H NMR spectrum of syn-ReO(d-TMCAATH2) exhibited changes in two pH regions, consistent with sequential protonation of the amine and of the carboxylic group. These experimental and MM results reinforce previous hypotheses about the factors favoring one syn form in one ionization state of M(V)O(N2S2) compounds at physiological pH. [Copyright &y& Elsevier]

Describes the synthesis of rhenium(V) complexes with an open-chain quadridentate ligand containing two amine and two amido donors. Structural characterization of the compounds by x-ray crystallography; Determination of solution equilibria.