BORONIC ACID ADDUCTS OF TECHNETIUM DIOXIME (BATO) COMPLEXES DERIVED FROM QUINUCLIDINE BENZILATE (QNB) BORONIC ACID STEREOISOMERS - SYNTHESES AND STUDIES OF THEIR BINDING TO THE MUSCARINIC ACETYLCHOLINE-RECEPTOR

We have investigated the possibility of using BATO complexes derivatized with the muscarinic acetylcholine receptor (mAChR) antagonist, quinuclidinyl benzilate (QNB), for mAChR imaging. The BATO complexes, TcCl(DMG)(3)B-QNB, were prepared using QNB derivatives containing a 4'-boronic acid substituent on one of the benzilic benzene rings (QNB-boronic acid). The QNB-boronic acid molecule has two chiral centers, and all four QNB-BATO stereoisomers were made and evaluated. When studied using in vitro receptor binding assays based on tissue from rat brain caudate-putamen (which contains primarily M(1) and M(4) mAChR) and rat heart (M(2) mAChR), the QNB-boronic acid stereoisomers had binding affinities (K-A) in the range 2 x 10(5)-1 x 10(8), at least 10-fold lower than the K-A for QNB (ca 2 x 10(9)). The stereochemistry of both centers had some influence on the affinity constant. When the TcCl(DMG)(3)B-QNB complexes were studied, none of the stereoisomeric complexes displayed measurable specific binding (K-A < 10(6)), but all showed high non-specific binding. In vitro autoradiography with rat brain slices confirmed the absence of specific binding in these tracers. In vivo, the (TcCl)-Tc-99m(DMG)(3)B-QNB complexes displayed minimal brain uptake, and modest heart uptake; the latter was unlikely to be related to uptake by the mAChR. In light of these findings, we conclude that the interaction between the TcCl(DMG)(3)B-QNB complexes and biological membranes is dominated by the hydrophobicity of the BATO moiety. The TcCl(DMG)(3)B-QNB complexes, therefore, have little potential for mAChR imaging.