Polyamine ligands (L) have excellent binding characteristics for the formation of fac-99mTc(CO)3-based radiopharmaceuticals. Normally, these L are elaborated so as to leave pendant groups designed to impart useful biodistribution characteristics to the fac-[99mTc(CO)3L] imaging agent. Our goal is to lay a foundation for understanding the features of the bound elaborated ligands by using the fac-[Re(CO)3L]-analogue approach with the minimal prototypical ligands, diethylenetriamine (dien) or simple dien-related derivatives. Treatment of the fac-[Re(CO)3(H2O)3]+ cation with such triamine (NNN) ligands afforded fac-[Re(CO)3L]+ complexes. Ligand variations included having a central amine thioether donor, thus allowing X-ray crystallographic and NMR spectroscopic comparisons of fac-[Re(CO)3L]+ complexes with NNN and NSN ligands. fac-[Re(CO)3L]+ complexes with two terminal exo-NH groups exhibit unusually far upfield exo-NH NMR signals in DMSO-d6. Upon the addition of Cl-, these exo-NH signals move downfield, while the signals of any endo-NH or central NH groups move very little. This behavior is attributed to the formation of 1:1 ion pairs having selective Cl- hydrogen bonding to both exo-NH groups. Base addition to a DMSO-d6 solution of meso-exo-[Re(CO)3(N,N',N''-Me3dien)]PF6 led to isomerization of only one NHMe group, producing the chiral isomer. The meso isomer did not form. The [Re(CO)3(N,N,N',N'',N''-pentamethyldiethylenetriamine)]triflate.[Re(CO)3(mu3-OH)]4.3.35H2O crystal, the first structure with a fac-[Re(CO)3L] complex cocrystallized with this well-known cluster, provided parameters for a bulky NNN ligand and also reveals CO-CO interlocking intermolecular interactions that could stabilize the crystal.
Introduction:The first human studies of a characterized radiopharmaceutical containing a { 99m Tc (CO) 3 } + core, Na[ 99m Tc(CO) 3 (LAN)], demonstrated that Na[ 99m Tc(CO) 3 (LAN)] was an excellent renal imaging agent however, its clearance was less than that of 131 Iorthoiodohippurate ( 131 I-OIH) and it did not provide a direct measure of effective renal plasma flow. In order to develop a 99m Tc renal agent with pharmacokinetic properties equivalent to those of 131 I-OIH, we investigated the 99m Tc(CO) 3 /Re(CO) 3 complexes formed from carboxymethylmercaptosuccinic acid (CMSAH 3 ) and thiodisuccinic acid (TDSAH 4 ). Once the ligand is bound to 99m Tc(CO) 3 through a thioether and two carboxyl groups, the complexes have at least one unbound carboxyl group, essential for the interaction with the renal tubular transporter.Methods: X-ray crystal structural analysis of NMe 4 [Re(CO) 3 (CMSAH)] was performed to interpret the nature of 99m Tc tracers. CMSAH 3 and TDSAH 4 were radiolabeled by incubating each ligand and the precursor [ 99m Tc(CO) 3 (H 2 O) 3 ] + at 70 °C (pH 7) for 30 min. The products were purified by RP-HPLC and biodistribution studies were performed in Sprague-Dawley rats, with 131 I-OIH as an internal control at 10 and 60 min.Results: Radiolabeling CMSAH 3 and TDSAH 4 with the [ 99m TcCO) 3 (H 2 O) 3 ] + precursor gave products quantitatively. Analysis of the Re(CO) 3 complexes with the CMSAH 3 and TDSAH 4 ligands demonstrates that ligands are bound in 99m Tc /Re(CO) 3 complexes through a thioether and two deprotonated carboxyl groups (forming tridentate dianionic moieties, generally with two fivemembered chelate rings). Renal excretion at 60 min (activity in the urine as a percent of 131 I-OIH) was 68 ± 1% for Na 3 [ 99m Tc(CO) 3 (TDSA)], but was 98 ± 1% for Na 2 [ 99m Tc(CO) 3 (CMSA)]. Conclusion:In rats, Na 2 [ 99m Tc(CO) 3 (CMSA)] is extracted by the kidneys and eliminated in the urine almost as rapidly as 131 I-OIH; consequently Na 2 [ 99m Tc(CO) 3 (CMSA)] may provide a direct measure of effective renal plasma flow and further evaluation in humans is warranted.
Treatment of cis-Pt(Me2SO)2Cl2 with DNSH-tren afforded [Pt(DNSH-tren)Cl]Cl and with DNSH-dienH, under increasingly more basic conditions, led to Pt(DNSH-dienH)Cl(2), Pt(DNSH-dien)Cl, and Pt(DNS-dien). (DNSH = 5-(dimethylamino)naphthalene-1-sulfonyl, linked via a sulfonamide group to tris(2-aminoethyl)amine (DNSH-tren) and diethylenetriamine (DNSH-dienH); the H's in DNSH-dienH designate protons sometimes lost upon Pt binding, i.e., sulfonamide NH for the dienH moiety and H8 for the DNSH moiety). Respectively, the three neutral DNSH-dienH-derived complexes are difunctional, monofunctional, and nonfunctional and exhibit decreasing fluorescence in this order as the dansyl group distance to Pt decreases. 2D NMR data establish that Pt(DNS-dien) has a Pt-C8 bond and a Pt-N(sulfonamido) bond. Pt(DNSH-dien)Cl and [Pt(DNSH-tren)Cl]Cl bind to N7 of 6-oxopurines (e.g., 5'-GMP, 3'-IMP, and 9-ethylguanine) and sulfur of methionine (met). Competition and challenge reactions for Pt(II) with met and 5'-GMP typically reveal that met binding is favored kinetically but that 5'-GMP binding is favored thermodynamically. This common type of behavior was found for [Pt(DNSH-tren)Cl]Cl. In contrast, Pt(DNSH-dien)Cl had reduced kinetic selectivity for met. This unusual behavior undoubtedly arises as a consequence of the bound Pt-N(sulfonamido) group, which donates strongly to Pt (as indicated by relatively upfield dien NH signals) and which places the bulky DNSH moiety close to the monofunctional reaction site. The decrease in the relatively upfield shifts of the DNSH group signals indicates that this group stacks with the purine. This stacking could explain the unprecedented, relatively low reactivity of a Pt complex bearing a dien-type ligand toward met vs 5'-GMP.
To achieve a net-neutral coordination unit in radiopharmaceuticals with a fac-M(CO)3+ core (M = Tc, Re), facially coordinated monoanionic tridentate ligands are needed. New neutral fac-Re(CO)3L complexes were obtained by treating fac-[Re(CO)3(H2O)3]+ with unsymmetrical tridentate NNN donor ligands (LH) based primarily on a diethylenetriamine (dien) moiety with an aromatic group linked to a terminal nitrogen through a sulfonamide. LHs contain 2,4,6-trimethylbenzenesulfonyl (tmbSO2) and 5-(dimethylamino)naphthalene-1-sulfonyl (DNS) groups. X-ray crystallographic and NMR analyses confirm that in both the solid and the solution states all L- in fac-Re(CO)3L complexes are bound in a tridentate fashion with one donor being nitrogen from a deprotonated sulfonamido group. Another fundamental property that is important in radiopharmaceuticals is shape, which in turn depends on ring pucker. For L- = tmbSO2-dien-, tmbSO2-N'-Medien-, and tmbSO2-N,N-Me2dien-, the two chelate rings have a different pucker chirality, as is commonly found for a broad range of metal complexes. However, for fac-Re(CO)3(DNS-dien), both chelate rings have the same pucker chirality because the sulfonamido ring has an unusual pucker for the absolute configuration at Re; a finding that is attributable to intramolecular and intermolecular hydrogen bonds from the sulfonamido oxygens to the NH2 groups. Averaging of tmb NMR signals, even at -90 degrees C for Re(CO)3(tmbSO2-N,N-Me2dien), indicates rapid dynamic motion in the complexes with this group. However, examination of the structures suggests that free rotation about the S-C(tmb) bond is not possible but that concerted coupled rotations about the N-S and the S-C bonds can explain the NMR data.
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