NOVEL HEXAKIS(ARENEISONITRILE)TECHNETIUM(I) COMPLEXES AS RADIOLIGANDSTARGETED TO THE MULTIDRUG-RESISTANCE P-GLYCOPROTEIN

Transport substrates and modulators of the human multidrug resistance (MDR1) P-glycoprotein (Pgp) are generally lipophilic cationic compound s, many with substituted aryl moieties, We sought to synthesize aromat ic technetium-isonitrile complexes to enable functional detection in v ivo of Pgp expression in tissues. A series of substituted aromatic iso nitrile analogs were synthesized from their corresponding amines by re action with dichlorocarbene under phase transfer-catalyzed conditions, and the non-carrier-aaded hexakis(areneisonitrile)Tc-99m(I) complexes were produced by reaction with pertechnetate in the presence of sodiu m dithionite. Cellular accumulation in. vitro, whole body biodistribut ion, and the imaging properties of these lipophilic, monocationic orga nometallic complexes were determined in Chinese hamster lung fibroblas ts expressing MDR Pgp, in normal rats, and in rabbits, respectively. F or this initial series, verapamil (50 mu M), the classical Pgp modulat or, significantly enhanced cellular accumulation or displaced binding of Tc complexes of 1b, 1d, 1h, 2a, 2d, 3a, and 3b, indicative of targe ted interactions with Pgp. Most complexes, despite their modestly high lipophilicity, were excluded by the blood/brain barrier, and several complexes displayed simultaneously high hepatobiliary and renal excret ion in vivo, consistent with the physiological expression pattern of P gp in these tissues. Selected Tc- and Re-areneisonitrile complexes of this class have potential applicability to the functional imaging and modulation, respectively, of MDR Pgp in human tissues.