Novel hexakis(areneisonitrile)technetium(I) complexes as radioligands targeted to the multidrug resistance P-glycoprotein.
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.
Herman
L W
LW
Laboratory of Molecular Radiopharmacology, Mallinckrodt Institute of Radiology, Washington University Medical School, St. Louis, Missouri 63110, USA.
Sharma
V
V
Kronauge
J F
JF
Barbarics
E
E
Herman
L A
LA
Piwnica-Worms
D
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000494:pharmacology*; D000818:Animals; D006224:Cricetinae; D003412:Cricetulus; D018432:Drug Resistance, Multiple; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009570:Nitriles / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D017556:Technetium Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009570:Nitriles; D017556:Technetium Compounds