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Assessment of 18F-labeled mitochondrial complex I inhibitors as PET myocardial perfusion imaging agents in rats, rabbits, and primates

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

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 18F. These agents were evaluated for IC50 values, tissue biodistribution, and cardiac PET imaging. 18F-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 IC50 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 18F-RP1003, 2.40 ± 0.21 and 2.67 ± 0.27 for 18F-RP1004, and 2.28 ± 0.12 and 1.81 ± 0.17 for 18F-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 18F-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 99mTc-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 18F-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.

Conclusion

MC-I inhibitors have the potential to be a new class of MPI agent.

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Acknowledgments

We thank the Veterinary Science Group of Bristol Myers Squibb Medical Imaging for providing excellent animal care. Some of the data were presented at the American Heart Association Scientific Session in 2005.

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Authors and Affiliations

  1. Discovery Biology, Bristol Myers Squibb Medical Imaging, 331 Treble Cove Rd, N. Billerica, MA, 01862, USA

    Ming Yu, Mary Guaraldi, Mikhail Kagan, Mahesh Mistry, Jennifer McDonald, Jody Bozek, Padmaja Yalamanchili, Megan Hayes & Simon P. Robinson

  2. Discovery Chemistry, Bristol Myers Squibb Medical Imaging, 331 Treble Cove Rd, N. Billerica, MA, 01862, USA

    Michael Azure, Ajay Purohit, Heike Radeke & David S. Casebier

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  1. Ming Yu
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  2. Mary Guaraldi
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  13. Simon P. Robinson
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Correspondence to Simon P. Robinson.

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Yu, M., Guaraldi, M., Kagan, M. et al. Assessment of 18F-labeled mitochondrial complex I inhibitors as PET myocardial perfusion imaging agents in rats, rabbits, and primates. Eur J Nucl Med Mol Imaging 36, 63–72 (2009). https://doi.org/10.1007/s00259-008-0909-8

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  • DOI: https://doi.org/10.1007/s00259-008-0909-8

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