Molecular Imaging of Cardiovascular Infections with 6ʹʹ-[¹⁸F]-Fluoromaltotriose PET/CT

Objectives: Infective endocarditis (IE) is a devastating disease with high fatality rates. Staphylococci are the most common etiologic agents of endocarditis. While imaging plays an important component of diagnosing IE, existing modalities are substantially limited. Echocardiography may not be that sensitive in many cases, CT angiography requires ECG gating and IV contrast, and MRI cannot be used in patients with certain cardiac implantable devices. ¹⁸F-FDG PET/CT and leukocyte scintigraphy both image inflammation in or adjacent to sites of infection, and consequently have limited sensitivity and specificity, particularly in patients with recent surgery. To address this problem, we have developed a novel positron emission tomography (PET) tracer 6ʹʹ-[¹⁸F]Fluoromaltotriose, which is transported via the maltodextrin transporter, a transport system that is exclusive to bacteria and not present on mammalian cells. The purpose of this study was to investigate the diagnostic accuracy of 6ʹʹ-[¹⁸F]Fluoromaltotriose PET/CT imaging in a preclinical bacteria-induced endocarditis model.

Methods: 6ʹʹ-[¹⁸F]Fluoromaltotriose was synthesized with high radiochemical purity and evaluated in several clinically relevant bacterial strains in culture and in living mice. In the mouse endocarditis model, valve trauma was first induced by placing a 32-G catheter at the aortic root via the right carotid artery. Bioluminescent Staphylococcus aureus bacteria (strain Xen 36; 10⁶ CFUs) was injected via tail vain 24h after surgery. In vivo bioluminescence imaging (BLI) was performed using the IVIS Spectrum instrument (Perkin Elmer). 6ʹʹ-[¹⁸F]Fluoromaltotriose PET/CT imaging was then performed 24h later on a small-animal Inveon microPET/CT scanner (Siemens) for 60 minutes and quantitatively analyzed for tissue uptake and tracer kinetics. Lastly, the animals were euthanized after imaging, hearts and organs were removed, and processed for biodistribution analysis and microbial assessment or histology.

Results: In-vitro cell uptake studies showed that 6ʹʹ-[¹⁸F]Fluoromaltotriose was taken up by both Gram-positive and Gram-negative strains of bacteria and not by mammalian cell lines. In the Staphylococcus aureus-induced infective endocarditis mouse model, there was an approximate 2.5-fold higher mean tracer uptake in the infected mice hearts (n=6) when compared to the control mice (n=6) (4.20 ± 1.06 %ID/g vs. 1.75 ± 0.41 %ID/g; p<0.002). The range of the mean tracer uptake in the aortic valve region for the infected mice varied from 2.70-5.40 %ID/g while for the control mice it was 1.10-2.20 %ID/g tissue. The heart had the highest PET signal above the diaphragm, while the kidneys had the highest signal below the diaphragm. Within the heart, the PET signal from the infected aortic valve had the highest uptake and could be clearly seen; in some cases, the tricuspid valve was also infected. Moreover, the signal on the PET images was confirmed by post-mortem examination.

Conclusions: 6′′-[¹⁸F]Fluoromaltotriose was able to image valvular infection with high sensitivity and specificity. 6′′-[¹⁸F]Fluoromaltotriose promises to have significant diagnostic utility, with the potential to change the clinical management of patients suffering from infectious diseases of bacterial origin. Plans are currently underway to have this radiotracer translated into the clinic. Research Support: NIH 5T32EB009035-08