Synthesis and preliminary evaluation of 18F-labeled pyridaben analogues for myocardial perfusion imaging with PET.

UNLABELLED: In this study the (18)F-labeled pyridaben analogs 2-tertbutyl-4-chloro-5-(4-(2-(18)F-fluoroethoxy))benzyloxy-2H-pyridazin-3-one ((18)F-FP1OP) and 2-tertbutyl-4-chloro-5-(4-(2-(2-(2-(18)F-fluoroethoxy)ethoxy)ethoxy))benzyloxy-2H-pyridazin-3-one ((18)F-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 ((19)F-FP1OP and (19)F-FP3OP) were synthesized and characterized by infrared, (1)H nuclear magnetic resonance, (13)C nuclear magnetic resonance, and mass spectrometry analysis. (18)F-FP1OP and (18)F-FP3OP were obtained by 1-step nucleophilic substitution of tosyl with (18)F 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. (18)F-FP1OP had lower hydrophilicity and higher water stability than that of (18)F-FP3OP. In biodistribution studies, both (18)F-FP1OP and (18)F-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 (18)F-FP1OP showed that the heart uptake could be blocked effectively by rotenone or nonradioactive (19)F-FP1OP. Clear cardiac PET images of (18)F-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 (18)F-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 ((18)F-FP1OP) has better stability, faster clearance from the major organs, and a higher heart-to-liver ratio than the other tracer ((18)F-FP3OP). On the basis of the promising biologic properties, this mitochondrial complex I-targeted tracer ((18)F-FP1OP) is worthy to be developed as an MPI agent and to be compared with the other PET MPI agents in the future.