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European Journal of Nuclear Medicine and Molecular Imaging

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01-01-2009 | Original Article

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

Authors: Ming Yu, Mary Guaraldi, Mikhail Kagan, Mahesh Mistry, Jennifer McDonald, Jody Bozek, Padmaja Yalamanchili, Megan Hayes, Michael Azure, Ajay Purohit, Heike Radeke, David S. Casebier, Simon P. Robinson

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 1/2009

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.

Beller GA, Bergmann SR. Myocardial perfusion imaging agents: SPECT and PET. J Nucl Cardiol 2004;11:71–86.PubMedCrossRef

Garcia EV, Eisner RL, Patterson RE. What should we expect from cardiac PET? J Nucl Med 1993;34:978–80.PubMed

Schwaiger M, Melin J. Cardiological applications of nuclear medicine. Lancet 1999;354:661–6.PubMedCrossRef

Lin JW, Sciacca RR, Chou RL, Laine AF, Bergmann SR. Quantification of myocardial perfusion in human subjects using 82Rb and wavelet-based noise reduction. J Nucl Med 2001;42:201–8.PubMed

Yu M, Guaraldi MT, Mistry M, Kagan M, McDonald JL, Drew K, et al. BMS-747158-02: a novel PET myocardial perfusion imaging agent. J Nucl Cardiol 2007;14:789–98.PubMedCrossRef

Marshall RC, Powers-Risius P, Reutter BW, O’Neil JP, La Belle M, Huesman RH, et al. Kinetic analysis of 18F-fluorodihydrorotenone as a deposited myocardial flow tracer: comparison to 201Tl. J Nucl Med 2004;45:1950–9.PubMed

Marshall RC, Powers-Risius P, Reutter BW, Taylor SE, VanBrocklin HF, Huesman RH, et al. Kinetic analysis of 125I-iodorotenone as a deposited myocardial flow tracer: comparison with 99mTc-sestamibi. J Nucl Med 2001;42:272–81.PubMed

Okun JG, Lummen P, Brandt U. Three classes of inhibitors share a common binding domain in mitochondrial complex I (NADH:Ubiquinone Oxidoreductase). J Biol Chem 1999;274:2625–30.PubMedCrossRef

Schuler F, Yano T, Di Bernardo S, Yagi T, Yankovskaya V, Singer TP, et al. NADH-Quinone oxidoreductase: PSST subunit couples electron transfer from iron-sulfur cluster N2 to quinone. Proc Natl Acad Sci U S A 1999;96:4149–53.PubMedCrossRef

10.

Lindell SD, Ort O, Lummen P, Klein R. The design and synthesis of novel inhibitors of NADH:ubiquinone oxidoreductase. Bioorg Med Chem Lett 2004;14:511–4.PubMedCrossRef

11.

Barth E, Stammler G, Speiser B, Schaper J. Ultrastructural quantitation of mitochondria and myofilaments in cardiac muscle from 10 different animal species including man. J Mol Cell Cardiol 1992;24:669–81.PubMedCrossRef

12.

Yalamanchili P, Wexler E, Hayes M, Yu M, Bozek J, Kagan M, et al. Mechanism of uptake and retention of F-18 BMS-747158-02 in cardiomyocytes: a novel PET myocardial imaging agent. J Nucl Cardiol 2007;14:782–8.PubMedCrossRef

13.

Satoh T, Miyoshi H, Sakamoto K, Iwamura H. Comparison of the inhibitory action of synthetic capsaicin analogues with various NADH-ubiquinone oxidoreductases. Biochim Biophys Acta 1996;1273:21–30.PubMedCrossRef

14.

VanBrocklin HF, Hanrahan SM, Enas JD, Nandanan E, O’Neil JP. Mitochondrial avid radioprobes. Preparation and evaluation of 7’(Z)-[125I]iodorotenone and 7’(Z)-[125I]iodorotenol. Nucl Med Biol 2007;34:109–16.PubMedCrossRef

15.

Piwnica-Worms D, Kronauge JF, Chiu ML. Uptake and retention of hexakis (2-methoxyisobutyl isonitrile) technetium(I) in cultured chick myocardial cells. Mitochondrial and plasma membrane potential dependence. Circulation 1990;82:1826–38.PubMed

16.

Younes A, Songadele JA, Maublant J, Platts E, Pickett R, Veyre A. Mechanism of uptake of technetium-tetrofosmin. II: Uptake into isolated adult rat heart mitochondria. J Nucl Cardiol 1995;2:327–33.PubMedCrossRef

17.

Glover DK, Ruiz M, Yang JY, Smith WH, Watson DD, Beller GA. Myocardial 99mTc-tetrofosmin uptake during adenosine-induced vasodilatation with either a critical or mild coronary stenosis: comparison with 201Tl and regional myocardial blood flow. Circulation 1997;96:2332–8.PubMed

18.

Glover DK, Ruiz M, Edwards NC, Cunningham M, Simanis JP, Smith WH, et al. Comparison between 201Tl and 99mTc sestamibi uptake during adenosine-induced vasodilation as a function of coronary stenosis severity. Circulation 1995;91:813–20.PubMed

19.

Huisman MC, Higuchi T, Reder S, Nekolla SG, Poethko T, Wester HJ, et al. Initial characterization of an 18F-labeled myocardial perfusion tracer. J Nucl Med 2008;49:630–6.PubMedCrossRef

20.

Nekolla SG, Reder S, Higuchi T, Dzewas G, Poethko T, Preissl A, et al. Assessment of imaging properties of a new F-18 labelled flow tracer in a pig model. J Am Coll Cardiol 2008;51:A170.

21.

Hilton TC, Thompson RC, Williams HJ, Saylors R, Fulmer H, Stowers SA. Technetium-99m sestamibi myocardial perfusion imaging in the emergency room evaluation of chest pain. J Am Coll Cardiol 1994;23:1016–22.PubMedCrossRef

22.

Matsunari I, Tanishima Y, Taki J, Ono K, Nishide H, Fujino S, et al. Early and delayed technetium-99m-tetrofosmin myocardial SPECT compared in normal volunteers. J Nucl Med 1996;37:1622–6.PubMed

23.

Boz A, Gungor F, Karayalcin B, Yildiz A. The effects of solid food in prevention of intestinal activity in Tc-99m tetrofosmin myocardial perfusion scintigraphy. J Nucl Cardiol 2003;10:161–7.PubMedCrossRef

24.

Hurwitz GA, Clark EM, Slomka PJ, Siddiq SK. Investigation of measures to reduce interfering abdominal activity on rest myocardial images with Tc-99m sestamibi. Clin Nucl Med 1993;18:735–41.PubMedCrossRef

25.

Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 1998;19:26–37.PubMedCrossRef

Title: Assessment of 18F-labeled mitochondrial complex I inhibitors as PET myocardial perfusion imaging agents in rats, rabbits, and primates
Authors: Ming Yu
Mary Guaraldi
Mikhail Kagan
Mahesh Mistry
Jennifer McDonald
Jody Bozek
Padmaja Yalamanchili
Megan Hayes
Michael Azure
Ajay Purohit
Heike Radeke
David S. Casebier
Simon P. Robinson
Publication date: 01-01-2009
Publisher: Springer-Verlag
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 1/2009
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-008-0909-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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