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

Abstract

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.

Iminoether Complexes of the Type, fac‐[Re(CO)3L{HNC(CH3)OCH3}]BF4 (L = Bipyridine or a Substituted Bipyridine): Synthesis and Properties

“…The low reactivity of the alcohols tested versus the amines that were tested previously suggests that selective bioconjugation to the fac-{ 99m Tc(CO) 3 } + core through an amidine linkage is feasible for biomolecules that have both amine and hydroxy groups. Finally, a comparison of the CϵN bond lengths that were obtained for the fac-[Re(CO) 3 (CH 3 CN) 3 ]BF 4 /PF 6 complexes with those values obtained for other rhenium acetonitrile complexes revealed that there is no significant difference between the CϵN 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.…”

“…Our primary aim in the investigation of the synthesis and properties of complexes with a fac-{Re(CO) 3 } + core is the development of renal imaging agents with a fac-{ 99m Tc-(CO) 3 } + core. [1][2][3] This approach has led to the development of fac-{ 99m Tc(CO) 3 } + renal agents that have shown promising pharmacokinetic properties in humans.…”

“…[1][2][3] This approach has led to the development of fac-{ 99m Tc(CO) 3 } + renal agents that have shown promising pharmacokinetic properties in humans. [4,5] We have noted that there are some problems in utilizing water, which is the solvent that is used to prepare the common precursor, fac-[Re(CO) 3 (H 2 O) 3 ] + . [1] In water, the various pH conditions lead to different linkage isomers or mixtures of isomers for the complicated ligands.…”

“…[1] In water, the various pH conditions lead to different linkage isomers or mixtures of isomers for the complicated ligands. [2,3] In addition, it is inconvenient to monitor the formation of the complexes by NMR-spectroscopic methods under aqueous reaction conditions. Therefore, in order to overcome the above mentioned aqueous chemistry problems, we evaluated the use in the distortion of L and the methyl substituent position have little influence on the ease of iminoether formation.…”

“…Therefore, in order to overcome the above mentioned aqueous chemistry problems, we evaluated the use 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, and 2-propanol) decreases the ease of fac-[Re(CO) 3 (5,5Ј-Me 2 bipy){HNC(CH 3 )OR}]BF 4 formation. Isopropanol did not form the iminoether complex after two days of heating the reaction mixture at reflux.…”