Table 1 Additional examples of molecular imaging probes used to image viruses or processes resulting from viral infection. The table describes the general mechanisms of action of the probe, as well as key findings from studies that used it

PET/CT

[¹⁸F]F-AraG,

Activated T cells

HIV

Studied in combination with ⁸⁹ZR-VRC01. Found that there was a correlation between tissues with increased ⁸⁹ZR-VRC01 and [¹⁸F]F-AraG uptake in HIV-positive patients. In particular, [¹⁸F]F-AraG was increased in lymphatic tissues and the bone marrow¹³⁴.

PET/CT

⁸⁹Zr-Df-Crefmirlimab

CD8 + T cells

COVID-19

Crefmirlimab (or IAB22M2C) is a minibody that binds to CD8 + T cells. This study used total body PET to look at CD8 + T-cell distribution dynamics in convalescent COVID-19 patients. They found that the ratios of CD8 + T cells in tissue:blood increased in COVID-19 patients compared to the control group, with this trend increasing over time¹³⁵. A minibody was used over a full-sized antibody due to the small size, which has faster serum clearance¹³⁵.

PET/CT

[⁶⁴ Cu]NODAGA-CG34

CMKLR1— lung inflammation and injury

COVID-19, ARDS

CMKLR1 is involved in the recruitment of various immune cell populations to tissues. In the lungs specifically, this receptor has been shown to promote inflammation from irritants, infection, and injury, and in the case of COVID-19, it has been linked to macrophage recruitment leading to acute respiratory distress syndrome (ARDS). They found that CMKLR1 expression was 3X higher in COVID-19 patients compared to controls. In imaging of lung injuries, the authors report that regions of increased tracer uptake correlated to ground glass opacities seen on CT. Furthermore, treatment with dexamethasone in mice with LPS-induced lung damage resulted in decreased tracer uptake, indicating its specificity for lung inflammation¹³⁶.

PET/MRI

[¹⁸F]FEPPA

TSPO

Zika

FEPPA is a ligand for TSPO that can be used as a PET marker of neuroinflammation. A study on non-human primates found that [¹⁸F]FEPPA could identify CD68+ myeloid cells in the brain in an allograft model¹³⁷. A murine study on ZIKA found that of all immune cells present in the brain, only myeloid lineages showed increased TSPO compared to pre-infection. In the case of microglia specifically, there was a strong correlation between TSPO expression and [¹⁸F]FEPPA uptake⁷⁶.

PET/CT

[18 F]DPA-714

TSPO

COVID-19

TSPO is distributed throughout the body, thereby serving as a marker of inflammation in multiple regions. Lung lesions caused by COVID-19 infection are difficult to visualize using anatomical imaging unless they are severe. Therefore, using [18F]DPA-714 is promising in identifying lung lesions based on increased immune cell migration into damaged regions. It was noted in preliminary non-human primate studies that increased TSPO signal correlated to increased dendritic cell levels even in tissues showing no anatomical signs of lesions¹³⁸. Another group used [18 F]DPA-714 to look at neuroinflammation in long COVID patients. They found that those experiencing symptoms had substantially increased tracer uptake in the brain compared to matched healthy controls¹³⁹.

PET/MRI

[¹¹C]PBR28

TSPO

COVID-19

Glial cells can become activated in response to immune signals, but sustained activation can lead to disequilibrium between various cells of the brain. Persistent glial activation has been suggested as a possible component of neurological and vascular changes observed in long COVID. [¹¹C]PBR28 is a ligand for TSPO, previously discussed as a marker of neuroinflammation. Using [¹¹C]PBR28, large regions of increased uptake were observed in several brain regions, and the intensity of PET uptake in the brain correlated to markers of vasculature changes¹⁴⁰.

PET/CT

¹⁸F-α_vβ₆-BP

α_vβ₆

COVID-19

¹⁸F-α_vβ₆-BP is a probe designed to bind to the integrin α_vβ₆ α_vβ₆ is normally expressed at very low levels in healthy tissues; however, it is increased during tissue remodeling and fibrosis. This probe was tested on one patient approximately two months after COVID-19 recovery. Preliminary data found a good correlation between regions of increased ¹⁸F-α_vβ₆-BP and CT findings (ex: GGOs) of COVID-19-mediated lung damage¹⁴¹.

PET/CT

⁶⁸Ga-grazytracer

Granzyme B

Cardiac inflammation and myocardial infarction

Myocardial infarction (MI) has high morbidity and mortality rates, and can be triggered and linked to several different viral infections⁶⁴. Recently, CD8 + T cells that release granzyme B have been shown to contribute to myocardial inflammation, with increased levels of these cells occurring in MI. The tracer ⁶⁸Ga-grazytracer is a peptide-based tracer that selectively inhibits granzyme B via binding¹⁴². In rat models of MI, it was found that the tracer had the most accumulation in MI subjects compared to controls. This uptake corresponded to CD8 + . T cell and granzyme B levels were seen using immunohistochemistry¹⁴³.

BLI/FLI

nLuc and ZsGreen1 [ZsG]

rMA-EBOV

Ebola

Using reporter nLuc or ZsG coupled to rMA-EBOV (a recombinant reporter virus) was sufficient for tracking the Ebola virus in vivo and ex vivo. While single-reporter recombinant viruses are available, the use of a dual-reporter system had comparable viral attenuation. As FLI has reduced depth penetration compared to BLI, dual imaging can compensate for this. Conversely, as BLI imaging modalities are largely limited to small animals, including an FLI reporter can also make the probe applicable to other species (despite the need for ex vivo analysis for deeper tissues)¹⁴⁴.