[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 membrane potential (1-4). They are used as agents for myocardial-perfusion single-photon emission computed tomography and tumor imaging. However, the high accumulation of technetium 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 for the evaluation of myocardial blood flow by use of positron-emitting radionuclides (e.g., ⁸²RbCl, ¹³NH₃, and H₂¹⁵O). However, the majority of these radiotracers exhibit short physical half-lives (<20 min), and they cannot be distributed from a central radiopharmacy. Lipophilic cations, such as ¹¹C-labeled 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). MCI catalyzes the transfer of electrons from NADH to ubiquinone and translocates protons from the mitochondrial matrix to the intermembrane space to generate ATP and thereby the energy supply of the cell. MCI 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 use. 2-tert-Butyl-4-chloro-5-[4-(2-fluoroethoxymethyl)-benzyloxy]-2H-pyridazin-3-one (BMS-747158-01), an analog of the MCI inhibitor pyridaben (8), is found to be a potent MCI inhibitor with a hydrophobic heterocyclic pyridazinone moiety (9). 2-tert-Butyl-4-chloro-5-[4-(2-[¹⁸F]fluoroethoxymethyl)-benzyloxy]-2H-pyridazin-3-one (BMS-747158-02) has been synthesized and studied as a PET agent used to image myocardium.

[PubMed]

BMS-747158-02 was prepared by fluorination of the toluene sulfonate ester precursor followed by purification with high-performance liquid chromatography (9). Average radiochemical yield (decay-corrected) was ~25%. Radiochemical purity was >95% with specific activities of 57–204 TBq/mmol (1,550–5,500 Ci/mmol) at the end of synthesis.

[PubMed]

Yalamanchili et al. (9) reported that BMS-747158-01 inhibited MCI NADH oxidation in bovine heart submitochondrial particles with a 50% inhibition concentration value of 16.6 ± 3 nM, which was comparable to the reference inhibitors of MCI (i.e., rotenone (18.2 ± 6.7 nM), pyridaben (19.8 ± 2.6 nM), and deguelin (23.1 ± 1.5 nM)). BMS-747158-02 had a high uptake in neonatal rat cardiomyocytes with 10.3 ± 0.7% of the incubated dose at 60 min. Rotenone (200 nM) and deguelin (200 nM) inhibited tracer accumulation in cardiomyocytes by 91 ± 2% and 89 ± 3%, respectively. The uptake of BMS-747158-02 was rapid with a half-maximal uptake time of ~0.5 min, whereas its retention was excellent with a half-maximal washout for efflux of >120 min.

Yu et al. (10) measured heart uptake in an isolated rabbit heart model at flow rates of 1.66–5.06 ml/min per g wet left ventricular weight. The net BMS-747158-02 heart uptake increased proportionally (0.93 ± 0.15 to 2.44 ± 0.40 ml/min per g) and to a greater extent than that of ²⁰¹thallium (0.76 ± 0.02 to 1.11 ± 0.02 ml/min per g) or ^99mTc-sestamibi (0.49 ± 0.03 to 0.77 ± 0.08 ml/min per g).

[PubMed]

Maddahi et al. (12) estimated the human dosimetry of BMS-747158-02 in 13 healthy subjects after injection of 170-244 MBq (4.6-6.6 mCi) of BMS747158. The organ receiving the highest radiation dose was the kidney at 0.066 mSv/MBq (0.24 rem/mCi), followed by the heart wall at 0.048 mSv/MBq (0.18 rem/mCi). The mean effective dose was 0.019 mSv/MBq (0.072 rem/mCi) with mean urinary excretion of 4.83% ID.

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Yalamanchili P., Wexler E., Hayes M., Yu M., Bozek J., Kagan M., Radeke H.S., Azure M., Purohit A., Casebier D.S., Robinson S.P. Mechanism of uptake and retention of F-18 BMS-747158-02 in cardiomyocytes: a novel PET myocardial imaging agent. J Nucl Cardiol. 2007;14(6):782–8. [PubMed: 18022104]

10.

Yu M., Guaraldi M.T., Mistry M., Kagan M., McDonald J.L., Drew K., Radeke H., Azure M., Purohit A., Casebier D.S., Robinson S.P. BMS-747158-02: a novel PET myocardial perfusion imaging agent. J Nucl Cardiol. 2007;14(6):789–98. [PubMed: 18022105]

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Higuchi T., Nekolla S.G., Huisman M.M., Reder S., Poethko T., Yu M., Wester H.J., Casebier D.S., Robinson S.P., Botnar R.M., Schwaiger M. A new 18F-labeled myocardial PET tracer: myocardial uptake after permanent and transient coronary occlusion in rats. J Nucl Med. 2008;49(10):1715–22. [PubMed: 18794259]

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Maddahi J., Czernin J., Lazewatsky J., Huang S.C., Dahlbom M., Schelbert H., Sparks R., Ehlgen A., Crane P., Zhu Q., Devine M., Phelps M. Phase I, first-in-human study of BMS747158, a novel 18F-labeled tracer for myocardial perfusion PET: dosimetry, biodistribution, safety, and imaging characteristics after a single injection at rest. J Nucl Med. 2011;52(9):1490–8. [PubMed: 21849402]