Myocardial Perfusion Imaging (MPI) is a non-invasive procedure to provide a sensitive means for detection, localization, and risk satisfaction of ischemic heart disease, assessment of left ventricular function, and myocardial viability. MPI is one of the most commonly performed investigations in nuclear medicine studies. The most widely used MPI is single-photon emission computed tomography (SPECT), usually performed using single-photon radiopharmaceuticals, such as 99mTc-MIBI, 99mTc-tetrofosmin, and 201Tl-chloride [Sachdev et al., 1990; Kelly et al., 1993; Maddahi et al., 1994]. Unlike SPECT, positron emission tomography (PET) imaging offers several evident advantages of imaging in MPI application including higher spatial resolution, better sensitivity, and an improved attenuation correction. Currently, the used PET radiotracers for MPI studies are [13N]NH3, [15O]H2O, and 82Rb [Schelbert et al., 1981; Selwyn et al., 1982; Bergmann et al., 1984]. The short half-lives of PET tracers, such as 15O (2 min) and 13N (10 min), and the requirement for an on-site cyclotron for manufacturing these tracers are the main restrictions for their usage. Additionally, 82Sr/82Rb generator is broadly available but it is not an ultimate PET radiotracer because of its high recurring price, very short half-life combined with long positron range that lowers the image resolution. When compared with other PET tracers, fluorine-18 (18F) offers suitable nuclear and chemical properties for PET imaging [Okarvi 2001; Varagnolo et al., 2000]. Therefore, various 18F-labeled radiopharmaceuticals for MPI have been prepared and evaluated and some of these new agents have shown better image quality and a better association to true myocardial blood flow than 99mTc-MIBI [Marshall et al., 2004; Madar et al., 2006; Yu et al., 2007; Huisman et al., 2008; Shoup et al., 2011].
It has been shown that the rhodamine dyes are accumulated in mitochondria and take around 30% of the myocardial intracellular volume in the heart [Kronauge et al., 1992]. Thus, numerous 18F-rhodamines analogs as potential MPI agents were developed recently [Heinrich et al., 2010; Gottumukkala et al., 2010; Bartholoma et al., 2012]. In particular, 18F-labeled rhodamine B diethylene glycol ester ([18F]RhoBDEGF) has provided an excellent image quality and might be a potential PET tracer for MPI studies [Mark et al., 2013]. Recently, our group has developed [18F]-FDG-rhodamine, [124I]-SIB-rhodamine, and 68Ga-NOTA-rhodamine conjugates. These radioconjugates have demonstrated a high myocardial uptake and favorable pharmacokinetics which indicate that some of these radioconjugates may be useful for MPI studies [Aljammaz et al., 2014; Aljammaz et al., 2015; Aljammaz et al., 2019].
The cyclotron-produced positron emitter copper-64 (64Cu) together with its 12.7 h half-life and well-known coordination chemistry makes it one of the most attractive radionuclides for PET imaging [McCarthy et al., 1997; Alliot et al., 2011; Szelecsenyi et al., 1993]. Therefore, varieties of 64Cu-radiolabeled biomolecules for potential use beyond the measurement of glucose metabolism were developed and investigated [Anderson et al., 2009; Zhang et al., 2013; Sprague et al., 2007; Hao et al., 2009; Evangelista et al., 2013]. Among these, 64Cu-labeled DOTA-somatostatin conjugate (64Cu-DOTATATE) has been recently approved by the FDA for the localization of somatostatin receptor-positive neuroendocrine tumors (NETs) in adult patients. For the past several years, we are interested in developing new agents for MPI studies; in this paper, we described the synthesis and initial evaluation of the 64Cu-NOTA- and 64Cu-NOTAM-rhodamine conjugates.