RÉSUMÉ
A series of potent and selective ß1-adrenoreceptor ligands were identified (IC50 range, 0.04-0.25 nM; ß1/ß2 selectivity range, 65-450-fold), labeled with the PET radioisotope fluorine-18 and evaluated in normal Sprague-Dawley rats. Tissue distribution studies demonstrated uptake of each radiotracers from the blood pool into the myocardium (0.48-0.62% ID/g), lung (0.63-0.97% ID/g), and liver (1.03-1.14% ID/g). Dynamic µPET imaging confirmed the in vivo dissection studies.
RÉSUMÉ
A series of fluorinated pyridazinone derivatives with IC50 values ranging from 8 to 4000 nM for the mitochondrial complex 1 (MC1) have been prepared. Structure-activity relationship (SAR) assessment indicated preference of the fluorine label to be incorporated on an alkyl side chain rather than directly on the pyridazinone moiety. Tissue distribution studies of a series of analogues ([18F] 22-28) in Sprague-Dawley (SD) rats identified [18F]27 as the most promising radiotracer with high uptake in cardiac tissue (3.41%ID/g; 30 min post injection) in addition to favorable heart to nontarget organ distribution ratios. MicroPET images of SD rats and nonhuman primates after [18F]27 administration allowed easy assessment of the myocardium through 60 min with minimal lung or liver interference.
Sujet(s)
Coeur/imagerie diagnostique , Pyridazines/synthèse chimique , Radiopharmaceutiques/synthèse chimique , Animaux , Bovins , Complexe I de la chaîne respiratoire/antagonistes et inhibiteurs , Femelle , Radio-isotopes du fluor , Techniques in vitro , Macaca mulatta , Mâle , Mitochondries du myocarde/enzymologie , Tomographie par émission de positons , Pyridazines/composition chimique , Pyridazines/pharmacocinétique , Radiopharmaceutiques/composition chimique , Radiopharmaceutiques/pharmacocinétique , Rats , Rat Sprague-Dawley , Relation structure-activité , Distribution tissulaireRÉSUMÉ
A series of fluorinated chromone analogs with IC50 values ranging from 9 to 133 nM for the mitochondrial complex 1 (MC-I) has been prepared. A structure-activity relationship (SAR) study of the most potent fluorinated chromone analog 10 demonstrated the linkage heteroatom preference of the side chain region of the molecule while maintaining potent MC-I inhibitory activity. Tissue distribution studies 30 min after [(18)F]10 administration to Sprague-Dawley (SD) rats demonstrated high uptake of the radiotracer from the blood pool into the myocardium (2.24% ID/g), kidney (1.93% ID/g), and liver (2.00% ID/g). After 2 h about 66% of the activity in the myocardium at 30 min had been retained, whereas approximately 70% had been cleared from the liver and kidney. MicroPET images of SD rats after [(18)F]10 administration allowed easy assessment of the myocardium through 60 min with minimal lung or liver interference.
Sujet(s)
4H-1-Benzopyran-4-ones/synthèse chimique , Complexe I de la chaîne respiratoire/antagonistes et inhibiteurs , Radio-isotopes du fluor , Coeur/imagerie diagnostique , Radiopharmaceutiques/synthèse chimique , Sulfures/synthèse chimique , Animaux , Bovins , 4H-1-Benzopyran-4-ones/composition chimique , 4H-1-Benzopyran-4-ones/pharmacocinétique , Techniques in vitro , Marquage isotopique , Rein/imagerie diagnostique , Rein/métabolisme , Foie/imagerie diagnostique , Foie/métabolisme , Poumon/imagerie diagnostique , Poumon/métabolisme , Mâle , Myocarde/métabolisme , Tomographie par émission de positons , Radiopharmaceutiques/composition chimique , Radiopharmaceutiques/pharmacocinétique , Rats , Rat Sprague-Dawley , Relation structure-activité , Particules submitochondriales/effets des médicaments et des substances chimiques , Particules submitochondriales/enzymologie , Sulfures/composition chimique , Sulfures/pharmacocinétique , Technétium (99mTc) sestamibi/pharmacocinétique , Distribution tissulaireRÉSUMÉ
A solid-phase synthesis of trisubstituted 1H-pyrido[2,3-d]pyrimidin-4-ones has been developed. The synthesis utilizes solid-phase bound N-2,6-dichloronicotinoyl-1H-benzotriazole-1-carboximidamides as key intermediates. Sequential substitution of benzotriazole and the two chlorines furnishes the title compounds with regioselectivity and high purity. Application of the method to various disubstituted analogues is also demonstrated.