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Theranostics 2017; 7(2):413-424. doi:10.7150/thno.15712 This issue Cite

Research Paper

Noninvasive Imaging of Myocardial Inflammation in Myocarditis using ⁶⁸Ga-tagged Mannosylated Human Serum Albumin Positron Emission Tomography

Seung-Pyo Lee^1,2*, Hyung-Jun Im^3*, Shinae Kang⁴, Seock-Jin Chung³, Ye Seul Cho¹, Hyejeong Kang¹, Ho Seon Park⁴, Do-Won Hwang³, Jun-Bean Park^1,2, Jin-Chul Paeng³, Gi-Jeong Cheon³, Yun-Sang Lee³, Jae Min Jeong^3#✉, Yong-Jin Kim^1,2#✉

1. Cardiovascular Center, Seoul National University Hospital;
2. Department of Internal Medicine, Seoul National University College of Medicine;
3. Department of Nuclear Medicine, Seoul National University Hospital and Seoul National University College of Medicine;
4. Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
*These authors contributed equally as first authors.
#These authors contributed equally as corresponding authors.

✉ Corresponding author: Jae Min Jeong, PhD. Department of Nuclear Medicine, Seoul National University Hospital and Seoul National University College of Medicine, Daehak-ro 101, Jongno-gu, Seoul, South Korea, 03080. E-mail: jmjngac.kr AND Yong-Jin Kim, MD, PhD. Cardiovascular Center, Seoul National University Hospital and Department of Internal Medicine, Seoul National University College of Medicine, Daehak-ro 101, Jongno-gu, Seoul, South Korea, 03080. Tel: 82-2-2072-1963 FAX: 82-2-2072-2577 E-mail: kimdamasac.kr. More

Abstract

The diagnosis of myocarditis traditionally relies on invasive endomyocardial biopsy but none of the imaging studies so far are specific for infiltration of the inflammatory cells itself. We synthesized ⁶⁸Ga-2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) mannosylated human serum albumin (MSA) by conjugating human serum albumin with mannose, followed by conjugation with NOTA and labeling it with ⁶⁸Ga. The efficacy of ⁶⁸Ga-NOTA-MSA positron emission tomography (PET) for imaging myocardial inflammation was tested in a rat myocarditis model. A significant number of mannose receptor-positive inflammatory cells infiltrated the myocardium in both human and rat myocarditis tissue. ⁶⁸Ga-NOTA-MSA uptake was upregulated in organs of macrophage accumulation, such as liver, spleen, bone marrow and myocardium (0.32 (0.31~0.33) for normal versus 1.02 (0.86~1.06) for myocarditis (median (range), SUV); n=4~6 per group, p-value=0.01). ⁶⁸Ga-NOTA-MSA uptake in the left ventricle was upregulated in myocarditis compared with normal rats (2.29 (1.42~3.40) for normal versus 4.18 (3.43~6.15) for myocarditis (median (range), average standard uptake value ratio against paraspinal muscle); n=6 per group, p-value<0.01), which was downregulated in rats with cyclosporine-A treated myocarditis (3.69 (2.59~3.86) for myocarditis versus 2.28 (1.76~2.60) for cyclosporine-A treated myocarditis; n=6 per group, p-value<0.01). The specificity of the tracer was verified by administration of excess non-labeled MSA. ⁶⁸Ga-NOTA-MSA uptake was significantly enhanced earlier in the evolution of myocarditis before any signs of inflammation could be seen on echocardiography. These results demonstrate the potential utility of visualizing infiltration of mannose receptor-positive macrophages with ⁶⁸Ga-NOTA-MSA PET in the early diagnosis of as well as in the monitoring of treatment response of myocarditis.

Keywords: myocarditis, macrophage, mannose receptor, positron emission tomography, molecular imaging.

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