Structure-activity relationship and preclinical evaluation of carbon-11-labeled ammonium salts as PET-myocardial perfusion imaging agents

Background: Due to the limited availability of suitable positron emission tomography (PET) tracers, the majority of myocardial perfusion imaging (MPI) scans is performed using SPECT rather than PET. Aim: The aimof this study is to design and synthesize carbon-11-labeled ammoniumsalt derivatives and explore their structure-activity relationship (SAR) and their potential as PET-MPI agents. Methods and Results: Three carbon-11-labeled ammonium salts were developed. SAR of the labeled compounds were explored vis-à-vis the effects of charge density and lipophilicity on the distribution kinetics in mice. These studies pointed at [¹¹C]4 as the lead compound. Comparative microPET/CT scans in healthy rats, using both [¹¹C]4 and [¹³N]-NH3, substantiated the potential of [¹¹C]4 ([ ¹¹C]-DMDPA). A proof of concept for the potential of radiolabeled ammonium salts as MPI agents has been demonstrated in a newly developed swine model of permanent partial coronary artery occlusion. Conclusions: SAR studies of ¹¹C-labeled ammonium salts suggest that both lipophilicity and charge density affect the performance of these compounds as MPI probes. In a swine model, the labeled lead successfully visualized the defect regions in the myocardium. The data presented call for the development of fluorine-18 analogues, to increase clinical impact.