[18F]F-AraG

Myocardial infarction (MI) with subsequent inflammation is one of the most common heart conditions leading to progressive tissue damage. A reliable imaging marker to assess tissue viability after MI would help determine the risks and benefits of any intervention. In this study, we investigate whether a new mitochondria-targeted imaging agent, ¹⁸F-labeled 2'-deoxy-2'-¹⁸F-fluoro-9-β-d-arabinofuranosylguanine ([¹⁸F]F-AraG), a positron emission tomography (PET) agent developed for imaging activated T cells, is suitable for cardiac imaging and to test the myocardial viability after MI.

To test whether the myocardial [¹⁸F]-F-AraG signal is coming from cardiomyocytes or immune infiltrates, we compared cardiac signal in wild-type (WT) mice with that of T cell deficient Rag1 knockout (Rag1 KO) mice. We assessed the effect of dietary nucleotides on myocardial [¹⁸F]F-AraG uptake in normal heart by comparing [¹⁸F]F-AraG signals between mice fed with purified diet and those fed with purified diet supplemented with nucleotides. The myocardial viability was investigated in rodent model by imaging rat with [¹⁸F]F-AraG and 2-deoxy-2[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) before and after MI. All PET signals were quantified in terms of the percent injected dose per cc (%ID/cc). We also explored [¹⁸F]FDG signal variability and potential T cell infiltration into fibrotic area in the affected myocardium with H&E analysis.

The difference in %ID/cc for Rag1 KO and WT mice was not significant (p = ns) indicating that the [¹⁸F]F-AraG signal in the myocardium was primarily coming from cardiomyocytes. No difference in myocardial uptake was observed between [¹⁸F]F-AraG signals in mice fed with purified diet and with purified diet supplemented with nucleotides (p = ns). The [¹⁸F]FDG signals showed wider variability at different time points. Noticeable [¹⁸F]F-AraG signals were observed in the affected MI regions. There were T cells in the fibrotic area in the H&E analysis, but they did not constitute the predominant infiltrates.

Our preliminary preclinical data show that [¹⁸F]F-AraG accumulates in cardiomyocytes indicating that it may be suitable for cardiac imaging and to evaluate the myocardial viability after MI.

Immunotherapies, especially checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) antibodies, have transformed cancer treatment by enhancing the immune system's capability to target and kill cancer cells. However, predicting immunotherapy response remains challenging. ¹⁸F-arabinosyl guanine ([¹⁸F]F-AraG) is a molecular imaging tracer targeting activated T cells, which may facilitate therapy response assessment by noninvasive quantification of immune cell activity within the tumor microenvironment and elsewhere in the body. The aim of this study was to obtain preliminary data on total-body pharmacokinetics of [¹⁸F]F-AraG as a potential quantitative biomarker for immune response evaluation. Methods: The study consisted of 90-min total-body dynamic scans of 4 healthy subjects and 1 non-small cell lung cancer patient who was scanned before and after anti-PD-1 immunotherapy. Compartmental modeling with Akaike information criterion model selection was used to analyze tracer kinetics in various organs. Additionally, 7 subregions of the primary lung tumor and 4 mediastinal lymph nodes were analyzed. Practical identifiability analysis was performed to assess the reliability of kinetic parameter estimation. Correlations of the SUV_mean, the tissue-to-blood SUV ratio (SUVR), and the Logan plot slope (K _Logan) with the total volume of distribution (V _T) were calculated to identify potential surrogates for kinetic modeling. Results: Strong correlations were observed between K _Logan and SUVR with V _T, suggesting that they can be used as promising surrogates for V _T, especially in organs with a low blood-volume fraction. Moreover, practical identifiability analysis suggested that dynamic [¹⁸F]F-AraG PET scans could potentially be shortened to 60 min, while maintaining quantification accuracy for all organs of interest. The study suggests that although [¹⁸F]F-AraG SUV images can provide insights on immune cell distribution, kinetic modeling or graphical analysis methods may be required for accurate quantification of immune response after therapy. Although SUV_mean showed variable changes in different subregions of the tumor after therapy, the SUVR, K _Logan, and V _T showed consistent increasing trends in all analyzed subregions of the tumor with high practical identifiability. Conclusion: Our findings highlight the promise of [¹⁸F]F-AraG dynamic imaging as a noninvasive biomarker for quantifying the immune response to immunotherapy in cancer patients. Promising total-body kinetic modeling results also suggest potentially wider applications of the tracer in investigating the role of T cells in the immunopathogenesis of diseases.