TY - JOUR T1 - Synthesis and Preliminary Evaluation of <sup>18</sup>F-Labeled Pyridaben Analogues for Myocardial Perfusion Imaging with PET JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 472 LP - 479 DO - 10.2967/jnumed.111.088096 VL - 53 IS - 3 AU - Tiantian Mou AU - Zuoquan Zhao AU - Wei Fang AU - Cheng Peng AU - Feng Guo AU - Boli Liu AU - Yunchuan Ma AU - Xianzhong Zhang Y1 - 2012/03/01 UR - http://jnm.snmjournals.org/content/53/3/472.abstract N2 - In this study the 18F-labeled pyridaben analogs 2-tertbutyl-4-chloro-5-(4-(2-18F-fluoroethoxy))benzyloxy-2H-pyridazin-3-one (18F-FP1OP) and 2-tertbutyl-4-chloro-5-(4-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy))benzyloxy-2H-pyridazin-3-one (18F-FP3OP) were synthesized, characterized, and evaluated as potential myocardial perfusion imaging (MPI) agents with PET. Methods: The tosylate labeling precursors of 2-tert-butyl-4-chloro-5-(4-(2-tosyloxy-ethoxy))-benzyloxy-2H-pyridazin-3-one (OTs-P1OP), 2-tert-butyl-4-chloro-5-(4-(2-(2-(2-tosyloxy-ethoxy)ethoxy)ethoxy))-benzyloxy-2H-pyridazin-3-one (OTs-P3OP), and the corresponding nonradioactive compounds (19F-FP1OP and 19F-FP3OP) were synthesized and characterized by infrared, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and mass spectrometry analysis. 18F-FP1OP and 18F-FP3OP were obtained by 1-step nucleophilic substitution of tosyl with 18F and evaluated as MPI agents in vitro (physicochemical properties, stability), ex vivo (autoradiography), and in vivo (toxicity and biodistribution in normal mice; cardiac PET in healthy Chinese mini swine and in acute myocardial infarction and chronic myocardial ischemia models). Results: The total radiosynthesis time of both tracers, including final high-pressure liquid chromatography purification, was about 70–90 min. Typical decay-corrected radiochemical yields were about 50%, and the radiochemical purities were more than 98% after purification. 18F-FP1OP had lower hydrophilicity and higher water stability than that of 18F-FP3OP. In biodistribution studies, both 18F-FP1OP and 18F-FP3OP had high heart uptake (31.13 ± 6.24 and 31.10 ± 3.72 percentage injected dose per gram at 2 min after injection, respectively) and high heart-to-liver, heart-to-lung, and heart-to-blood ratios at all time points after injection. Further autoradiography evaluation of 18F-FP1OP showed that the heart uptake could be blocked effectively by rotenone or nonradioactive 19F-FP1OP. Clear cardiac PET images of 18F-FP1OP were obtained in healthy Chinese mini swine at 2, 15, 30, 60, and 120 min after injection, and the uptake of perfusion deficit areas was much lower than in normal tissue in both acute myocardial infarction and chronic myocardial ischemia models. Conclusion: The 18F-labeled pyridaben analogs reported in this study have high heart uptake and low background uptake in both the mouse model and the Chinese mini swine model. The tracer with the shorter radiolabeling side chain (18F-FP1OP) has better stability, faster clearance from the major organs, and a higher heart-to-liver ratio than the other tracer (18F-FP3OP). On the basis of the promising biologic properties, this mitochondrial complex I–targeted tracer (18F-FP1OP) is worthy to be developed as an MPI agent and to be compared with the other PET MPI agents in the future. ER -