2- tert-Butyl-4-chloro-5-[4-(2-[18F]fluoro-ethoxymethyl)-benzyloxy]-3-(2 H)-pyridazinone

Excerpt

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 (^99mTcMIBI) and ^99mTc-tetrofosmin are delocalized lipophilic cations, which are rapidly taken up into cells driven by mitochondrial metabolism and membrane potential (1-4). They are used as myocardial-perfusion single-photon emission computed tomography (SPECT) as well as tumor imaging agents. 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 to evaluating myocardial blood flow by use of positron-emitting radionuclides (e.g. ⁸²RbCl, ¹³NH₃, and H₂¹⁵O). However, the majority of these radiotracers exhibited 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 (MC1) of the mammalian electron transfer chain is composed of at least 43 protein subunits, of which 7 are encoded by mitochondrial DNA (7). MC1 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. MC1 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-tert-Butyl-4-chloro-5-[4-(2-fluoro-ethoxymethyl)-benzyloxy]-3-(2H)-pyridazinone (MC1-27) is found to be a potent MC1 inhibitor with a hydrophobic heterocyclic chromone core (8). 2-tert-Butyl-4-chloro-5-[4-(2-[¹⁸F]fluoro-ethoxymethyl)-benzyloxy]-3-(2H)-pyridazinone ([¹⁸F]MC1-27) has been synthesized to study as a myocardium imaging PET agent.