title: Delineation of the border zone of ischemic rabbit myocardium by a technetium-labeled nitroimidazole.
abstract: Delineation of viable ischemic myocardium is an important problem in nuclear cardiology. To determine the feasibility of using a technetium-labeled nitroimidazole as an indicator of ischemic myocardium at risk of infarction, we characterized the distribution of a 2-nitroimidazole-derivatized PnAO ligand and its 99mTc complex, 99mTcO(PnAO)-1-CH2-(2NI) (BMS-181321) in the ischemic territory of the left anterior descending (LAD) coronary artery of the rabbit. In preliminary experiments, the performance of 14C-deoxyglucose (14C-2DG) and 14C-misonidazole was assessed relative to apparent regional relative myocardial blood flow (rMBF) indicated by 99mTc-teboroxime using double-label autoradiography in the rabbit LAD occlusion model. After demonstrating that 14C-2DG and 14C-misonidazole are selectively retained in the lateral border of the ischemic territory, BMS-181321 was co-injected intravenously, with either 14C-2DG or 14C-misonidazole, 20 min after LAD occlusion. In a separate experiment, 99mTcO(PnAO)-6-CH3, a complex with the same lipophilicity (log k' 0.26 vs. 0.31) as BMS-181321 but which lacks the 2NI moiety, was co-injected with 14C-2DG. After 30 min, the rabbits were sacrificed and 14C/99mTc autoradiograms were obtained from the same tissue sections. The autoradiograms revealed that BMS-181321 was retained with the same microregional distribution as both 14C-2DG and 14C-misonidazole in the border zone of the ischemic LAD territory. The selective retention of BMS-181321 depends on the presence of the nitroimidazole group, since 99mTcO(PnAO)-6-CH3 has a uniformly low myocardial distribution in contrast to the enhanced uptake of co-injected 14C-2DG. These data demonstrate that BMS-181321 is selectively retained in hypoxic myocardium and demarcates the ischemic border zone in a manner similar to 14C-2DG and 14C-misonidazole.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Di Rocco
authors.forename: A A
authors.initials: AA
authors.lastname: Bauer
authors.forename: J P
authors.initials: JP
authors.lastname: Pirro
authors.forename: B L
authors.initials: BL
authors.lastname: Kuczynski
authors.forename: L
authors.initials: L
authors.lastname: Belnavis
authors.forename: Y W
authors.initials: YW
authors.lastname: Chan
authors.forename: K E
authors.initials: KE
authors.lastname: Linder
authors.forename: R K
authors.initials: RK
authors.lastname: Narra
authors.forename: D P
authors.initials: DP
authors.lastname: Nowotnik
authors.forename: A D
authors.initials: AD
authors.lastname: Nunn
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000493:pharmacokinetics; D001345:Autoradiography; D003847:Deoxyglucose / Q000493:pharmacokinetics; D006321:Heart / Q000000981:diagnostic imaging*; D006439:Hemodynamics; D007091:Image Processing, Computer-Assisted; D008297:Male; D008920:Misonidazole / Q000493:pharmacokinetics; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging* / Q000503:physiopathology; D009593:Nitroimidazoles; D015609:Organotechnetium Compounds; D011817:Rabbits; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals
chemical_list: D000963:Antimetabolites; D009593:Nitroimidazoles; D015609:Organotechnetium Compounds; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; C082027:BMS 181321; D008920:Misonidazole; D003847:Deoxyglucose