Radiotracers for Molecular Imaging of Angiotensin-Converting Enzyme 2

Figures

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  Figure 1. Historical timeline of discoveries and molecular imaging for the major renin-angiotensin system (RAS) system components. Discoveries of RAS components are shown in blue. Discoveries of radiotracers for RAS components are shown in purple. Discoveries of the role of ACE2 in RAS are shown in green. Coronavirus pandemics are shown in brown. ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzymes 2; Ang, angiotensin; AT1R, angiotensin type 1 receptor; AT2R, angiotensin type 2 receptor; MasR, Mas receptor.

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  Figure 2. The renin-angiotensin system pathway mainly consists of angiotensin-converting enzyme ACE/angiotensin (Ang) II/angiotensin type 1 receptor (AT1R) axis and its counterbalancing ACE2/Ang-(1–7)/Mas axis. AT2R, angiotensin type 2 receptor. The dotted lines indicate the non-classical arms of the RAS.

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  Figure 3. ACE2 expression in human organs. Red asterisk (*) indicates ACE2 deficiency only hypothesized. Image from Salamanna, F.; Maglio, M.; Landini, M.P.; Fini, M. Body localization of ACE-2: on the trail of the keyhole of SARS-CoV-2. Front. Med. (Lausanne). 2020, 7, 594495 is licensed under CC BY 4.0 (http://creativecommons.org/licenses/by/4.0) [107].

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  Figure 4. DX-600-based radiopharmaceuticals. DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. NOTA: 1,4,7-triazacyclononane-1,4,7-triacetic acid. HYNIC: hydrazinonicotinic acid. NODAGA: 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid. HBED-CC: N,N′-bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid.

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  Figure 5. Representative positron emission tomography images of 68Ga-HZ20 in male and female volunteers. (A) Radioactivity uptake in a 38-year-old male volunteer at 90 min post-injection. 1: nasal mucosa, 2: gallbladder, 3: renal cortex, 4: small intestine, 5: testis. (B) Radioactivity uptake in a 34-year-old female volunteer at 90 min post-injection. 1: nasal mucosa, 2: breast, 3: gallbladder, 4: renal cortex, 5: left ovary. White arrows indicate regions of interest in (A,B). (C) Immunohistochemistry analysis of angiotensin-converting enzyme-2 expression in normal human organs (10×). Image from Zhu, H.; Zhang, H.; Zhou, N.; Ding, J.; Jiang, J.; Liu, T.; Liu, Z.; Wang, F.; Zhang, Q.; Zhang, Z.; et al. Molecular PET/CT profiling of ACE2 expression in vivo: implications for infection and outcome from SARS-CoV-2. Adv. Sci. 2021, 8, e2100965 is licensed under CC BY 4.0 (http://creativecommons.org/licenses/by/4.0) [93].

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  Figure 6. Representative positron emission tomography (PET) images of 68Ga-HZ20 in a volunteer recovered from COVID-19 infection. (A) The whole-body PET image and (B–D) axial PET/computed tomography (CT) (top panel: CT, middle panel: PET) images of nasal, lung, and testis, respectively, at 90 min post-injection were shown. (E) kidney uptake of 68Ga-HZ20 in a patient recovered from COVID (P), a healthy male (M), and a female (F) volunteer at 90 min post-injection. Arrows indicate regions of interest in (B–E). Image from Zhu, H.; Zhang, H.; Zhou, N.; Ding, J.; Jiang, J.; Liu, T.; Liu, Z.; Wang, F.; Zhang, Q.; Zhang, Z.; et al. Molecular PET/CT profiling of ACE2 expression in vivo: implications for infection and outcome from SARS-CoV-2. Adv. Sci. 2021, 8, e2100965 is licensed under CC BY 4.0 is licensed under CC BY 4.0 (http://creativecommons.org/licenses/by/4.0) [93].

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  Figure 7. Chemical structures of MLN-4760, [18F]F-MLN-4760, and [18F]F-Aza-MLN-4760. RCY, radiochemical yield.

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  Figure 8. Representative single photon emission computed tomography/computed tomography images of human embryonic kidney-ACE2/ACE xenograft-bearing mice obtained 1 h and 3 h post-injection of the radiopeptides. (A) 67Ga-DOTA-DX600, (B) 67Ga-NODAGA-DX600, and (C) 67Ga-HBED-CC-DX600. Image from Beyer, D.; Vaccarin, C.; Deupi, X.; Mapanao, A.K.; Cohrs, S.; Sozzi-Guo, F.; Grundler, P.V.; van der Meulen, N.P.; Wang, J.; Tanriver, M.; et al. A tool for nuclear imaging of the SARS-CoV-2 entry receptor: molecular model and preclinical development of ACE2-selective radiopeptides. EJNMMI Res. 2023, 13, 32 is licensed under CC BY 4.0 (http://creativecommons.org/licenses/by/4.0) [138].

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  Figure 9. Micro-single photon emission computed tomography/computed tomography imaging of 177Lu-HZ20 in (B1) HepG2ACE2+, (B2) blocked HepG2ACE2+ and (B3) HepG2WT tumor-bearing mice 60 min post-injection. The yellow arrow (T) indicates the tumor xenograft, the white arrow (K) indicates the kidney, (B) indicates the bladder, (H) indicates the heart, and (G) indicates the gallbladder. Image adapted from Zhang, Q.; Liu, T.; Ding, J.; Zhou, N.; Yu, Z.; Ren, Y.; Qin, X.; Du, P.; Yang, Z.; Zhu, H. Evaluation of (68)Ga- and (177)Lu-labeled HZ20 angiotensin-converting enzyme 2-targeting peptides for tumor-specific imaging. Mol. Pharm. 2022, 19, 4149–4156. Used with permission from The American Chemical Society [132].