Cyclic 68Ga-Labeled Peptides for Specific Detection of Human Angiotensin-Converting Enzyme 2.

In this study, we developed angiotensin-converting enzyme 2 (ACE2)-specific, peptide-derived 68Ga-labeled radiotracers, motivated by the hypotheses that ACE2 is an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility and that modulation of ACE2 in coronavirus disease 2019 (COVID-19) drives severe organ injury. Methods: A series of NOTA-conjugated peptides derived from the known ACE2 inhibitor DX600 were synthesized, with variable linker identity. Since DX600 bears 2 cystine residues, both linear and cyclic peptides were studied. An ACE2 inhibition assay was used to identify lead compounds, which were labeled with 68Ga to generate peptide radiotracers (68Ga-NOTA-PEP). The aminocaproate-derived radiotracer 68Ga-NOTA-PEP4 was subsequently studied in a humanized ACE2 (hACE2) transgenic model. Results: Cyclic DX-600-derived peptides had markedly lower half-maximal inhibitory concentrations than their linear counterparts. The 3 cyclic peptides with triglycine, aminocaproate, and polyethylene glycol linkers had calculated half-maximal inhibitory concentrations similar to or lower than the parent DX600 molecule. Peptides were readily labeled with 68Ga, and the biodistribution of 68Ga-NOTA-PEP4 was determined in an hACE2 transgenic murine cohort. Pharmacologic concentrations of coadministered NOTA-PEP (blocking) showed a significant reduction of 68Ga-NOTA-PEP4 signals in the heart, liver, lungs, and small intestine. Ex vivo hACE2 activity in these organs was confirmed as a correlate to in vivo results. Conclusion: NOTA-conjugated cyclic peptides derived from the known ACE2 inhibitor DX600 retain their activity when N-conjugated for 68Ga chelation. In vivo studies in a transgenic hACE2 murine model using the lead tracer, 68Ga-NOTA-PEP4, showed specific binding in the heart, liver, lungs and intestine-organs known to be affected in SARS-CoV-2 infection. These results suggest that 68Ga-NOTA-PEP4 could be used to detect organ-specific suppression of ACE2 in SARS-CoV-2-infected murine models and COVID-19 patients.

Nuclear Imaging of Bacterial Infection: The State of the Art and Future Directions.

Increased mortality rates from infectious diseases is a growing public health concern. Successful management of acute bacterial infections requires early diagnosis and treatment, which are not always easy to achieve. Structural imaging techniques such as CT and MRI are often applied to this problem. However, these methods generally rely on secondary inflammatory changes and are frequently not specific to infection. The use of nuclear medicine techniques can add crucial complementary information, allowing visualization of infectious pathophysiology beyond morphologic imaging. This review will discuss the current structural and functional imaging techniques used for the diagnosis of bacterial infection and their roles in different clinical scenarios. We will also present several new radiotracers in development, with an emphasis on probes targeting bacteria-specific metabolism. As highlighted by the current coronavirus disease 2019 epidemic, caused by the novel severe acute respiratory syndrome coronavirus 2, similar thinking may apply in imaging viral pathogens; for this case, prominent effects on host proteins, most notably angiotensin-converting enzyme 2, might also provide worthwhile imaging targets.