Assessment of 18F-labeled mitochondrial complex I inhibitors as PET myocardial perfusion imaging agents in rats, rabbits, and primates.
OBJECTIVE
Myocardial extractions of mitochondria complex I (MC-I) inhibitors were high and well correlated with flow. This study assessed the potential of MC-I inhibitors to be developed as myocardial perfusion imaging (MPI) agents.


METHODS
RP1003, RP1004, and RP1005 representing three classes of MC-I inhibitor were synthesized and radio-labeled with (18)F. These agents were evaluated for IC(50) values, tissue biodistribution, and cardiac PET imaging. (18)F-RP1004 was further examined for first-pass extraction and by imaging in non-human primates (NHP) and rats following coronary ligation.


RESULTS
RP1003, RP1004, and RP1005 exhibited high MC-I inhibitory activity with IC(50) of 3.7, 16.7, and 14.4 nM. Heart uptakes in rats (percent injected dose per gram tissue) at 15 and 60 min after injection were 3.52 +/- 0.36 and 2.68 +/- 0.20 for (18)F-RP1003, 2.40 +/- 0.21 and 2.67 +/- 0.27 for (18)F-RP1004, and 2.28 +/- 0.12 and 1.81 +/- 0.17 for (18)F-RP1005. The heart to lung and liver uptake ratios were favorable for cardiac imaging with these agents. In isolated perfused rabbit hearts, the uptake of (18)F-RP1004 increased from 0.74 +/- 0.19 to 1.68 +/- 0.39 mL/min/g at flow rates of 1.66 to 5.06 mL/min/g. These values were higher than or similar to that of (99m)Tc-sestamibi. Cardiac imaging with these agents in rats and rabbits allowed visualization of the heart with minimal lung interference and rapid liver activity clearance. Imaging with (18)F-RP1004 also showed clear myocardium and marked liver activity washout in the NHP and clear detection of the perfusion-deficit area associated with left coronary artery ligation in the rat.


CONCLUSIONS
MC-I inhibitors have the potential to be a new class of MPI agent.
Yu
Ming
M
Discovery Biology, Bristol Myers Squibb Medical Imaging, 331 Treble Cove Rd, N. Billerica, MA 01862, USA.
Guaraldi
Mary
M
Kagan
Mikhail
M
Mistry
Mahesh
M
McDonald
Jennifer
J
Bozek
Jody
J
Yalamanchili
Padmaja
P
Hayes
Megan
M
Azure
Michael
M
Purohit
Ajay
A
Radeke
Heike
H
Casebier
David S
DS
Robinson
Simon P
SP
D000818:Animals; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006321:Heart / Q000000981:diagnostic imaging; D008253:Macaca mulatta / Q000378:metabolism; D008297:Male; D055414:Myocardial Perfusion Imaging; D009206:Myocardium / Q000378:metabolism; D049268:Positron-Emission Tomography; D011724:Pyridazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013194:Staining and Labeling; D014018:Tissue Distribution
D005462:Fluorine Radioisotopes; D011724:Pyridazines; C062482:pyridazine; D042967:Electron Transport Complex I