Factors Influencing the pKa of Ligated Amines and the Syn/Anti Isomerization in Cysteine-Based Re(V)O(N2S2) Radiopharmaceutical Analogues As Revealed by a Novel Dominant Tautomer in the Solid State

Hansen, Lory; Lipowska, Małgorzata; Meléndez, Enrique; Xu, Xiaolong; Hirota, Shun; Taylor, Ashby B.; Marzillï, Luigi G.

doi:10.1021/ic9906398

Cited by 19 publications

(44 citation statements)

References 24 publications

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“…The NH signals diminished in size and eventually disappeared. However, the shifts of the CH signals did not change with this increase in basicity, even at very high pH > 10.The relatively rapid NH/ND exchange indicates some NH deprotonation, because this process requires coordinated amine deprotonation 21,23,76. However, the absence of the shifting of the CH signals indicates deprotonation is not favorable enough to produce detectable amounts of NH-deprotonated complexes.…”

Section: Resultsmentioning

confidence: 92%

“…The use of 1 H NMR spectra to study Re I analogues of Tc I radiopharmaceuticals is less advanced than in the study of Re V analogues of Tc V radiopharmaceuticals 15,21,23,71-74. Here, we employed 1 H NMR spectra to provide needed evidence for assessing the overall geometry of the new fac -[Re(CO) 3 L] n complexes, especially when crystals could not be obtained.…”

Section: Resultsmentioning

confidence: 99%

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Coordination Modes of Multidentate Ligands infac-[Re(CO)₃(polyaminocarboxylate)] Analogues of^99mTc Radiopharmaceuticals. Dependence on Aqueous Solution Reaction Conditions

Lipowska¹,

He²,

Xu³

et al. 2010

Inorg. Chem.

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We study Re analogues of 99mTc renal agents to interpret previous results at the 99mTc tracer level. The relative propensities of amine donors vs. carboxylate oxygen donors of four L = polyaminocarboxylate ligands to coordinate in fac-[ReI(CO)3L]n complexes were assessed by examining the reaction of fac-[ReI(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, diethylenetriamine-N-malonic acid, and diethylenetriamine-N-acetic acid] 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-[ReI(CO)3L]n products with HPLC traces correlating well with known traces of the fac-[99mTcI(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 impractical in a clinical setting. One goal in investigating this Re chemistry is to identify conditions for avoiding this problem of mixtures in preparations of fac-[99mTcI(CO)3L]n renal tracers. After separation and isolation of the fac-[ReI(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 preparation, equilibration was facile (ca. one hour 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-[99mTcI(CO)3L]n agents consisting of a single tracer.

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Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Coordination Modes of Multidentate Ligands infac-[Re(CO)₃(polyaminocarboxylate)] Analogues of^99mTc Radiopharmaceuticals. Dependence on Aqueous Solution Reaction Conditions

Lipowska¹,

He²,

Xu³

et al. 2010

Inorg. Chem.

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“…To accomplish our goal, we initially explored renal agents with the [ 99m Tc(V)O] 3+ core, such as 99m TcO-mercaptoacetyltriglycine ( 99m TcO-MAG3) (2–5), 99m TcO-ethylenedicysteine ( 99m TcO-EC) (6) and 99m TcO-mercaptoacetamide-ethylenecysteine ( 99m TcO-MAEC) (7, 8). All of those agents gave excellent scintigraphic images, but their plasma clearances were still significantly less than that of 131 I-OIH.…”

Section: Introductionmentioning

confidence: 99%

^99mTc(CO)₃-Nitrilotriacetic Acid: A New Renal Radiopharmaceutical Showing Pharmacokinetic Properties in Rats Comparable to Those of ¹³¹I-OIH

Lipowska¹,

Marzillï²,

Taylor³

2009

J Nucl Med

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To develop a 99m Tc renal tracer with a capacity to measure effective renal plasma flow comparable to that of the clinical gold standard 131 I-o-iodohippurate ( 131 I-OIH) and superior to that of 99m TcO-mercaptoacetyltriglycine, which has a clearance only 50%260% that of 131 I-OIH, we investigated 99m Tc-tricarbonyl nitrilotriacetic acid (Na 2 [ 99m Tc(CO) 3 (NTA)]). This radiopharmaceutical, which is based on an aminopolycarboxylate ligand, is formed as a single species and has a dangling carboxylate group favoring tubular transport. Methods: Na 2 [ 99m Tc(CO) 3 (NTA)] was prepared by using commercially available NTA and an IsoLink kit and isolated by high-performance liquid chromatography. The stability of Na 2 [ 99m Tc(CO) 3 (NTA)] in isotonic saline was assessed for 24 h and was further evaluated by incubation in 0.1 M cysteine and histidine for 4 h at 37°C. The biodistribution of Na 2 [ 99m Tc (CO) 3 (NTA)], coinjected with 131 I-OIH as an internal control, was evaluated in 5 normal Sprague-Dawley rats at 10 min, 5 normal Sprague-Dawley rats at 60 min (group A), and 6 rats with renal pedicle ligation at 60 min (group B) after injection. Clearance and extraction fraction studies were conducted in 2 normal Sprague-Dawley rats, and urine and plasma from 2 additional normal rats each were analyzed for metabolites by high-performance liquid chromatography. Results: The radiochemical purity of Na 2 [ 99m Tc(CO) 3 (NTA)] was greater than 99%, the complex was stable for 24 h at physiologic pH, and the challenge experiments showed no degradation. In normal rats, the percentage dose in the urine at 10 and 60 min was 108% 6 9% and 101% 6 5%, respectively, that of 131 I-OIH; minimal hepatic or gastrointestinal activity was demonstrated. In group B rats, Na 2 [ 99m Tc(CO) 3 (NTA)] was better retained in the blood and had less excretion into the bowel than did 131 I-OIH (P , 0.01). The plasma clearances of Na 2 [ 99m Tc(CO) 3 (NTA)] and 131 I-OIH were comparable, but the extraction fraction of Na 2 [ 99m Tc(CO) 3 (NTA)] was 93.5% 6 3.8%, compared with 67.9% 6 6.1% for 131 I-OIH. Plasma protein binding of Na 2 [ 99m Tc(CO) 3 (NTA)] averaged 67% 6 7%, and red cell uptake was 7% 6 2%. Conclusion: Na 2 [ 99m Tc (CO) 3 (NTA)] is stable, exists as a single species, and has pharmacodynamic properties in rats comparable to those of 131 I-OIH.Key Words: 99m Tc-tricarbonyl; renal radiopharmaceuticals; 99m Tc(CO) 3 (NTA); 131 I-ortho-iodohippurate ( 131 I-OIH); 99m Tcmercaptoacetyltriglycine ( 99m

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“…For example, dangling uncoordinated carboxyl groups (which are negatively charged and deprotonated at physiological pH) usually become neutral protonated groups in procedures employed to crystallize the complex 1,2,20-22. One goal of our study is to interpret how NMR spectra inform us about the solution structure of fac -[Re(CO) 3 L] n complexes.…”

Section: Introductionmentioning

confidence: 99%

NH NMR Shifts of New Structurally Characterized fac-[Re(CO)₃(polyamine)]ⁿ⁺ Complexes Probed via Outer-Sphere Hydrogen-Bonding Interactions to Anions, Including the Paramagnetic [Re^IVBr₆]²⁻ Anion

et al. 2010

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fac-[Re I (CO) 3 L] n complexes serve as models for short-lived fac-[ 99m Tc I (CO) 3 L] imaging tracers (L = tridentate ligands forming two five-membered chelate rings defining the L face). Dangling groups on L, needed to achieve desirable biodistribution, complicate the NMR spectra, which are not readily understood. Using less complicated L, we found that NH groups (exo-NH) projecting toward the L face sometimes showed an upfield shift attributable to steric shielding of the exo-NH group from the solvent by the chelate rings. Our goal is to advance our ability to relate these spectral features to structure and to solution properties. To investigate whether exo-NH groups in six-membered rings exhibit the same effect and whether the presence of dangling groups alters the effect, we prepared new fac-[Re(CO) 3 L] n complexes that allow direct comparisons of exo-NH shifts for six-membered vs. five-membered chelate rings. New complexes were structurally characterized with the following L: dipn (N-3-(aminopropyl)-1,3-propanediamine); N'-Medipn (3,3′-diamino-Nmethyldipropylamine); N,N-Me 2 dipn (N,N-dimethyldipropylenetriamine); aepn (N-2-(aminoethyl)-1,3-propanediamine); trpn (tris-(3-aminopropyl)amine); and tren (tris-(2-aminoethyl)amine). In DMSO-d 6 , the upfield exo-NH signals were exhibited by all complexes, indicating that the rings sterically shield the exo-NH groups from bulky solvent molecules. This interpretation was supported by exo-NH signal shift changes caused by added halide and [ReBr 6 ] 2− anions, consistent with outer-sphere H-bond interactions between these anions and the exo-NH groups. For fac- [Re(CO) 3 (dipn)]PF 6 in acetonitrile-d 3 , the exo-NH signal shifted further downfield in the series, Cl − > Br − > I − , and the plateau in shift change required lower concentration for smaller anions. These results are consistent with steric shielding of the exo-NH groups by the chelate rings. Nevertheless, despite its size, the shape and the charge of [ReBr 6 ] 2− allowed the dianion to induce large upfield paramagnetic shifts of the exo-NH signal of fac-[Re(CO) 3 (dipn)]PF 6 . This dianion shows promise as an outer-sphere H-bonding paramagnetic shift reagent. 21 For both isomers in the solid state, the coordinated carboxyl group is deprotonated, whereas the dangling carboxyl group is protonated. Two types of terminal NH's were defined and unambiguously identified through the crystallography of the two isomers. In one isomer, the terminal amine has an endo-NH proton (defined as the proton projecting toward the carbonyl ligands, Figure 1) with a normal relatively downfield shift (5.84 ppm, DMSO-d 6 ) for a terminal secondary amine NH signal. In the other isomer, this amine has an exo-NH proton (defined as the proton projecting away from the carbonyl ligands, Figure 1). 21 The signal of this terminal secondary amine exo-NH proton was observed at a rather upfield position (5.36 ppm, DMSO-d 6 ). NIH Public AccessIn later studies, 24 We hypothesized that the shift differences might be attributable in ...

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Factors Influencing the pK_a of Ligated Amines and the Syn/Anti Isomerization in Cysteine-Based Re(V)O(N₂S₂) Radiopharmaceutical Analogues As Revealed by a Novel Dominant Tautomer in the Solid State

Cited by 19 publications

References 24 publications

Coordination Modes of Multidentate Ligands infac-[Re(CO)₃(polyaminocarboxylate)] Analogues of^99mTc Radiopharmaceuticals. Dependence on Aqueous Solution Reaction Conditions

Coordination Modes of Multidentate Ligands infac-[Re(CO)₃(polyaminocarboxylate)] Analogues of^99mTc Radiopharmaceuticals. Dependence on Aqueous Solution Reaction Conditions

^99mTc(CO)₃-Nitrilotriacetic Acid: A New Renal Radiopharmaceutical Showing Pharmacokinetic Properties in Rats Comparable to Those of ¹³¹I-OIH

NH NMR Shifts of New Structurally Characterized fac-[Re(CO)₃(polyamine)]ⁿ⁺ Complexes Probed via Outer-Sphere Hydrogen-Bonding Interactions to Anions, Including the Paramagnetic [Re^IVBr₆]²⁻ Anion

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Factors Influencing the pKa of Ligated Amines and the Syn/Anti Isomerization in Cysteine-Based Re(V)O(N2S2) Radiopharmaceutical Analogues As Revealed by a Novel Dominant Tautomer in the Solid State

Cited by 19 publications

References 24 publications

Coordination Modes of Multidentate Ligands infac-[Re(CO)3(polyaminocarboxylate)] Analogues of99mTc Radiopharmaceuticals. Dependence on Aqueous Solution Reaction Conditions

Coordination Modes of Multidentate Ligands infac-[Re(CO)3(polyaminocarboxylate)] Analogues of99mTc Radiopharmaceuticals. Dependence on Aqueous Solution Reaction Conditions

99mTc(CO)3-Nitrilotriacetic Acid: A New Renal Radiopharmaceutical Showing Pharmacokinetic Properties in Rats Comparable to Those of 131I-OIH

NH NMR Shifts of New Structurally Characterized fac-[Re(CO)3(polyamine)]n+ Complexes Probed via Outer-Sphere Hydrogen-Bonding Interactions to Anions, Including the Paramagnetic [ReIVBr6]2− Anion

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Factors Influencing the pK_a of Ligated Amines and the Syn/Anti Isomerization in Cysteine-Based Re(V)O(N₂S₂) Radiopharmaceutical Analogues As Revealed by a Novel Dominant Tautomer in the Solid State

Coordination Modes of Multidentate Ligands infac-[Re(CO)₃(polyaminocarboxylate)] Analogues of^99mTc Radiopharmaceuticals. Dependence on Aqueous Solution Reaction Conditions

Coordination Modes of Multidentate Ligands infac-[Re(CO)₃(polyaminocarboxylate)] Analogues of^99mTc Radiopharmaceuticals. Dependence on Aqueous Solution Reaction Conditions

^99mTc(CO)₃-Nitrilotriacetic Acid: A New Renal Radiopharmaceutical Showing Pharmacokinetic Properties in Rats Comparable to Those of ¹³¹I-OIH

NH NMR Shifts of New Structurally Characterized fac-[Re(CO)₃(polyamine)]ⁿ⁺ Complexes Probed via Outer-Sphere Hydrogen-Bonding Interactions to Anions, Including the Paramagnetic [Re^IVBr₆]²⁻ Anion