Transport substrates and modulators of the human multidrug resistance (MDR1) P-glycoprotein
(Pgp) are generally lipophilic cationic compounds, many with substituted aryl moieties.
We sought to synthesize aromatic technetium-isonitrile complexes to enable functional
detection in vivo of Pgp expression in tissues. A series of substituted aromatic isonitrile
analogs were synthesized from their corresponding amines by reaction with dichlorocarbene
under phase transfer-catalyzed conditions, and the non-carrier-added hexakis(areneisonitrile)Tc-99m(I)
complexes were produced by reaction with pertechnetate in the presence of sodium dithionite.
Cellular accumulation in vitro, whole body biodistribution, and the imaging properties
of these lipophilic, monocationic organometallic complexes were determined in Chinese
hamster lung fibroblasts expressing MDR Pgp, in normal rats, and in rabbits, respectively.
For this initial series, verapamil (50 microM), the classical Pgp modulator, significantly
enhanced cellular accumulation or displaced binding of Tc complexes of 1b, 1d, 1h,
2a, 2d, 3a, and 3b, indicative of targeted 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 excretion
in vivo, consistent with the physiological expression pattern of Pgp 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.