We demonstrate that a tertiary sulfonamide group, N(SO2R)R′2, can re-hybridize to form a M–N bond of normal length even when the group is in a linear tridentate ligand, such as in the new tridentate N(SO2R)dpa ligands derived from di-(2-picolyl)amine (N(H)dpa). N(SO2R)dpa ligands were used to prepare fac-[Re(CO)3(N(SO2R)dpa)](PF6 or BF4) complexes. Structural characterization of the new complexes established that the tertiary sulfonamide nitrogen atom binds to Re with concomitant sp2-to-sp3 re-hybridization, facilitating facial coordination. The new fac-[Re(CO)3(N(SO2R)dpa)]X structures provide the only examples for any metal with the sulfonamide as part of a noncyclic linear tridentate ligand and with a normal metal-to-nitrogen(tertiary sulfonamide) bond length. Rare previous examples of such normal M–N bonds have been found only in more constrained situations, such as with tripodal tetradentate ligands. Our long-term objectives for the new tridentate N(SO2R)dpa ligands are to develop the fundamental chemistry relevant to the eventual use of the fac-[MI(CO)3]+ core (M = 99mTc, 186/188Re) in imaging and therapy. The sulfonamide group uniquely contributes to two of our goals: expanding ways to conjugate the fac-[MI(CO)3]+ core to biological molecules and also developing new symmetrical tridentate ligands that can coordinate facially to this core. Tests of our conjugation method, conducted by linking the fac-[ReI(CO)3]+ core to a new tetraarylporphyrin (T(N(SO2C6H4)dpa)P) as well as to a dansyl (5-(dimethylamino)naphthalene-1-sulfonyl) group, demonstrate that large molecular fragments can be tethered via a coordinated tertiary sulfonamide linkage to this core.

Treatment of two precursors, fac-[Re(CO)3(L)(CH3CN)]BF4 [L = 5,5′-dimethyl-2,2′-bipyridine (5,5′-Me2bipy) (1) and 6,6′-dimethyl-2,2′-bipyridine (6,6′-Me2bipy) (2)], with five C2-symmetrical saturated heterocyclic amines yielded ten new amidine complexes, fac-[Re(CO)3(L)(HNC(CH3)N(CH2CH2)2Y)]BF4 [Y = CH2, (CH2)2, (CH2)3, NH or O]. All ten complexes possess the novel feature of having only one isomer (amidine E configuration), as established by crystallographic and 1H NMR spectroscopic methods. We are confident that NMR signals of the other possible isomer (amidine Z configuration) would have been detected, if it were present. Isomers are readily detected in closely related amidine complexes because the double-bond character of the amidine C–N3 bond (N3 is bound to Re) leads to slow E to Z isomer interchange. The new fac-[Re(CO)3(L)(HNC(CH3)N(CH2CH2)2Y)]BF4 complexes have C–N3 bonds with essentially identical double-bond character. However, the reason that the Z isomer is so unstable as to be undetectable in the new complexes is undoubtedly because of unfavorable clashes between the equatorial ligands and the bulky N(CH2CH2)2Y ring moiety of the axial amidine ligand. The amidine formation reactions in acetonitrile (25 °C) proceeded more easily with 2 than with 1, indicating that the distortion in 6,6′-Me2bipy resulting from the proximity of the methyl substituents to the inner coordination sphere enhanced the reactivity of the coordinated CH3CN. Reaction times for 1 and 2 exhibited a similar dependence on the basicity and ring size of the heterocyclic amine reactants. Moreover, when the product of the reaction of 1 with piperidine, fac-[Re(CO)3(5,5′-Me2bipy)(HNC(CH3)N(CH2CH2)2CH2)]BF4, was challenged in acetonitrile-d3 or CDCl3 with a fivefold excess of the strong 4-dimethylaminopyridine ligand, there was no evidence for replacement of the amidine ligand after two months, thus establishing that the piperidinylamidine ligand is a robust ligand. This chemistry offers promise as a suitable means for preparing isomerically pure conjugated fac-[99mTc(CO)3L]n+/− imaging agents, including conjugates with known bioactive heterocyclic amines.

The methyl acetimidate (an iminoether) complexes, fac‐[Re(CO)3L{HNC(CH3)OCH3}]BF4 [where L = 2,2′‐bipyridine (bipy), 4,4′‐Me2bipy, 5,5′‐Me2bipy, or 6,6′‐Me2bipy], were formed when fac‐[Re(CO)3(CH3CN)3]BF4 in acetonitrile/methanol was treated with 2,2′‐bipyridine (bipy) or the dimethyl‐2,2′‐bipyridines (4,4′‐Me2bipy, 5,5′‐Me2bipy, or 6,6′‐Me2bipy). Structural analysis of the four fac‐[Re(CO)3L{HNC(CH3)OCH3}]BF4 complexes revealed that all of the complexes crystallize with the iminoether ligand in the Z configuration and that distortions in L that involved the two pyridyl rings are minor except for 6,6′‐Me2bipy, which is highly distorted. This distortion of the 6,6′‐Me2bipy ligand is reflected in the NMR‐spectroscopic data. Upon complex formation, the methyl group signal in the 13C NMR spectrum shifted downfield significantly for 6,6′‐Me2bipy, but this did not occur in the 13C NMR spectrum of the 5,5′‐Me2bipy complex. The reaction times for forming the respective fac‐[Re(CO)3L{HNC(CH3)OCH3}]BF4 complexes for these two ligands were comparable, which indicated that the differences in the distortion of L and the methyl substituent position have little influence on the ease of iminoether formation. However, a higher steric bulk of the alcohol (methanol, ethanol, and2‐propanol) decreases the ease of fac‐[Re(CO)3(5,5′‐Me2bipy){HNC(CH3)OR}]BF4 formation. Isopropanol did not form the iminoether complex after two days of heating the reaction mixture at reflux. The low reactivity of the alcohols tested versus the amines that were tested previously suggests that selective bioconjugation to the fac‐{99mTc(CO)3}+ core through an amidine linkage is feasible for biomolecules that have both amine and hydroxy groups. Finally, a comparison of the C≡N bond lengths that were obtained for the fac‐[Re(CO)3(CH3CN)3]BF4/PF6 complexes with those values obtained for other rhenium acetonitrile complexes revealed that there is no significant difference between the C≡N bond lengths and that there is no correlation to the acetonitrile reactivity. It is possible that the fac‐{Re(CO)3}+ core stabilizes the transition state for amine or alcohol addition.

Figure 1: Top view of the virtual environment, with call-outs for four out of the eight locations on the map. For each trial, the user first received a textual description of a location. Then, on the island (c), the user visited one of eight different places with different types of sensory feedback. We designed the island with particular scene features, including trains (boxed in pink on the map), orange trees (yellow), helicopters (white), and a waterfall (blue). We mapped sensory feedback (vision, audio, wind, floor vibration, and smell) to the scene features and varied them, depending on the study condition.

We previously identified two new agents based on the [99mTcVO]3+ core with renal clearances in human volunteers 30% higher than that of the widely used clinical tracer 99mTc-MAG3 (MAG35− = penta-anion of mercaptoacetyltriglycine). However, renal agents with even higher clearances are needed. More recently, we changed our focus from the [99mTcVO]3+ core to the discovery of superior tracers based on the fac-[99mTcI(CO)3]+ core. Compared to 99mTc-MAG3, fac-[99mTcI(CO)3(NTA)]2− (NTA3− = tri-anion of nitrilotriacetic acid) holds great promise by virtue of its efficient renal clearance via tubular secretion and the absence of hepatobiliary elimination, even in patients with severely reduced renal function. We report here NMR, molecular (X-ray) structure, and solution data on fac-[ReI(CO)3(NTA)]2− with a –CH2CO2− dangling monoanionic chain and on two fac-[ReI(CO)3(L)]− analogs with either a –CH2CONH2 or –CH2CH2OH dangling neutral chain. In these three fac-[ReI(CO)3(L)]n− complexes, the fac-[ReI(CO)3(N(CH2CO2)2)]− moiety is structurally similar and has similar electronic properties (as assessed by NMR data). In reported and ongoing studies, the two fac-[99mTcI(CO)3(L)]− analogs with these neutral dangling chains were found to have pharmacokinetic properties very closely similar to those of fac-[99mTcI(CO)3(NTA)]2−. Therefore, we reach the unexpected conclusion that in fac-[99mTcI(CO)3(L)]n− agents, renal clearance is affected much more than anticipated by features of the core plus the chelate rings (the [99mTcI(CO)3(N(CH2CO2)2)]− moiety) than by the presence of a negatively charged dangling carboxylate chain.