[PubMed]

Lipophilic cations are capable of passing through biological membranes by passive diffusion into the cytoplasm and mitochondria of cells in response to large negative plasma and mitochondrial membrane potentials. ^99mTc-2-Methoxyisobutylisonitrile (^99mTc-MIBI) and ^99mTc-tetrofosmin are delocalized lipophilic cations, which are rapidly taken up into cells driven by metabolic demand and membrane potential (1-4). They are used as myocardial-perfusion single-photon emission computed tomography agents and as tumor-imaging agents. However, the high accumulation of Tc tracers in the lung and liver may interfere with the detection of flow abnormalities in the myocardium. More recently, positron emission tomography (PET) imaging has emerged as an alternative approach to evaluate myocardial blood flow with the use of positron-emitting radionuclides (e.g., ⁸²RbCl, ¹³NH₃, and H₂¹⁵O). However, the majority of these radiotracers exhibit short physical half-lives (<10 min). Lipophilic cations such as [¹¹C]triphenylmethylphosphonium ([¹¹C]TPMP) (5) and 4-[¹⁸F]fluorobenzyl-triphenylphosphonium ([¹⁸F]FBnTP) have been investigated as PET agents for myocardial and tumor imaging (6).

Mitochondrial complex I (MCI) of the mammalian electron transfer chain is composed of at least 43 protein subunits, of which seven are encoded by mitochondrial DNA (7). MC-I catalyzes the transfer of electrons from NADH to ubiquinone and translocates protons from the mitochondrial matrix to the intermembrane space to generate ATP and thus the energy supply of the cell. MC-I may also play direct roles in the mitochondrial permeability transition and in cell death pathways. Myocardium has a high mitochondrial content because of high energy usage. 2-(4-(4-[¹⁸F]Fluoro-butyl)-benzylsulfanyl)-3-methyl-chromen-4-one ([¹⁸F]RP1005) has been found to be a potent MC-I inhibitor with a hydrophobic heterocyclic chromone (8) and its use as a PET agent for imaging myocardium is being studied.

[PubMed]

[¹⁸F]RP1005 was prepared as described by Yu et al. (8). [¹⁸F]Fluoride/Kryptofix 2.2.2/K₂CO₃ and the tosylate precursor were heated in acetonitrile for 30 min at 90°C, followed by high-performance liquid chromatography purification. Total synthesis time was 90 min. Radiochemical purity was >90%, with specific activities of 27.8–55.5 GBq/µmol (0.75–1.5 Ci/µmol) at the end of synthesis.

[PubMed]

Yu et al. (8) reported that RP1005 inhibited NADH oxidation by bovine heart submitochondrial particles with a 50% inhibition concentration (IC₅₀) value of 14.4 nM. The IC₅₀ value of the known MC-I inhibitor rotenone was 18.2 nM.

[PubMed]

No publication is currently available.

1.

Chernoff D.M., Strichartz G.R., Piwnica-Worms D. Membrane potential determination in large unilamellar vesicles with hexakis(2-methoxyisobutylisonitrile)technetium(I). Biochim Biophys Acta. 1993;1147(2):262–6. [PubMed: 8476920]

2.

Chiu M.L., Kronauge J.F., Piwnica-Worms D. Effect of mitochondrial and plasma membrane potentials on accumulation of hexakis (2-methoxyisobutylisonitrile) technetium(I) in cultured mouse fibroblasts. J Nucl Med. 1990;31(10):1646–53. [PubMed: 2213187]

3.

Molteni S.N., Seregni E., Botti C., Martinetti A., Ferrari L., Crippa F., Bombardieri E. The breast cancer cell line MCF7 as a model of 99mTc-SestaMIBI, 99mTc-tetrofosmin and 99mTc-Medronate incorporation. Anticancer Res. 1999;19(1A):255–9. [PubMed: 10226551]

4.

Younes A., Songadele J.A., 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(4):327–33. [PubMed: 9420807]

5.

Krause B.J., Szabo Z., Becker L.C., Dannals R.F., Scheffel U., Seki C., Ravert H.T., Dipaola A.F. Jr, Wagner H.N. Jr. Myocardial perfusion with [11C]methyl triphenyl phosphonium: measurements of the extraction fraction and myocardial uptake. J Nucl Biol Med. 1994;38(3):521–6. [PubMed: 7865551]

6.

Madar I., Ravert H.T., Du Y., Hilton J., Volokh L., Dannals R.F., Frost J.J., Hare J.M. Characterization of Uptake of the New PET Imaging Compound 18F-Fluorobenzyl Triphenyl Phosphonium in Dog Myocardium. J Nucl Med. 2006;47(8):1359–1366. [PubMed: 16883017]

7.

Lenaz G., Fato R., Genova M.L., Bergamini C., Bianchi C., Biondi A. Mitochondrial Complex I: structural and functional aspects. Biochim Biophys Acta. 2006;1757(9-10):1406–20. [PubMed: 16828051]

8.

Yu M., Guaraldi M., Kagan M., Mistry M., McDonald J., Bozek J., Yalamanchili P., Hayes M., Azure M., Purohit A., Radeke H., Casebier D.S., Robinson S.P. 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. 2009;36(1):63–72. [PubMed: 18716773]