title: 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.
abstract: 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)3B-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 M1 and M4 mAChR) and rat heart (M2 mAChR), the QNB-boronic acid stereoisomers had binding affinities (KA) in the range 2 x 10(5)-1 x 10(8), at least 10-fold lower than the KA for QNB (ca 2 x 10(9)). The stereochemistry of both centers had some influence on the affinity constant. When the TcCl(DMG)3B-QNB complexes were studied, none of the stereoisomeric complexes displayed measurable specific binding (KA < 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 99mTcCl(DMG)3B-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)3B-QNB complexes and biological membranes is dominated by the hydrophobicity of the BATO moiety. The TcCl(DMG)3B-QNB complexes, therefore, have little potential for mAChR imaging.
authors.affiliation: Diagnostics Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Jurisson
authors.forename: J
authors.initials: J
authors.lastname: Pirro
authors.forename: R J
authors.initials: RJ
authors.lastname: DiRocco
authors.forename: K C
authors.initials: KC
authors.lastname: Rosenspire
authors.forename: E
authors.initials: E
authors.lastname: Jagoda
authors.forename: P
authors.initials: P
authors.lastname: Nanjappan
authors.forename: W C
authors.initials: WC
authors.lastname: Eckelman
authors.forename: D P
authors.initials: DP
authors.lastname: Nowotnik
authors.forename: A D
authors.initials: AD
authors.lastname: Nunn
mesh_terms: D000818:Animals; D001345:Autoradiography; D001897:Boronic Acids / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D015394:Molecular Structure; D009206:Myocardium / Q000378:metabolism; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D011813:Quinuclidinyl Benzilate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D001897:Boronic Acids; D015609:Organotechnetium Compounds; D011976:Receptors, Muscarinic; C094947:technetium Tc 99m Cl(DMG)3B-QNB; D011813:Quinuclidinyl Benzilate