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 derivatiz ed with the muscarinic acetylcholine receptor (mAChR) antagonist, quin uclidinyl benzilate (QNB), for mAChR imaging. The BATO complexes, TcCl (DMG)(3)B-QNB, were prepared using QNB derivatives containing a 4'-bor onic acid substituent on one of the benzilic benzene rings (QNB-boroni c acid). The QNB-boronic acid molecule has two chiral centers, and all four QNB-BATO stereoisomers were made and evaluated. When studied usi ng in vitro receptor binding assays based on tissue from rat brain cau date-putamen (which contains primarily M(1) and M(4) mAChR) and rat he art (M(2) mAChR), the QNB-boronic acid stereoisomers had binding affin ities (K-A) in the range 2 x 10(5)-1 x 10(8), at least 10-fold lower t han the K-A for QNB (ca 2 x 10(9)). The stereochemistry of both center s had some influence on the affinity constant. When the TcCl(DMG)(3)B- QNB complexes were studied, none of the stereoisomeric complexes displ ayed measurable specific binding (K-A < 10(6)), but all showed high no n-specific binding. In vitro autoradiography with rat brain slices con firmed the absence of specific binding in these tracers. In vivo, the (TcCl)-Tc-99m(DMG)(3)B-QNB complexes displayed minimal brain uptake, a nd modest heart uptake; the latter was unlikely to be related to uptak e by the mAChR. In light of these findings, we conclude that the inter action between the TcCl(DMG)(3)B-QNB complexes and biological membrane s is dominated by the hydrophobicity of the BATO moiety. The TcCl(DMG) (3)B-QNB complexes, therefore, have little potential for mAChR imaging .