Comparison of <sup>68</sup>Ga-DOTA-Siglec-9 and <sup>18</sup>F-Fluorodeoxyribose-Siglec-9: Inflammation Imaging and Radiation Dosimetry

Virtanen, Helena; Silvola, Johanna M. U.; Autio, Anu; Li, Xiang-Guo; Liljenbäck, Heidi; Hellberg, Sanna; Siitonen, Riikka; Ståhle, Mia; Käkelä, Meeri; Airaksinen, Anu J.; Helariutta, Kerttuli; Tolvanen, Tuula; Veres, Tibor Z.; Saraste, Antti; Knuuti, Juhani; Jalkanen, Sirpa; Roivainen, Anne

doi:https://doi.org/10.1155/2017/7645070

Contrast Media & Molecular Imaging

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Abstract Introduction Materials and Methods Results Discussion Conclusion Conflicts of Interest Acknowledgments References Copyright Related Articles

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In Vivo Imaging of Inflammation and Infection

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Research Article | Open Access

Volume 2017 | Article ID 7645070 | https://doi.org/10.1155/2017/7645070

Comparison of ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-Fluorodeoxyribose-Siglec-9: Inflammation Imaging and Radiation Dosimetry

Helena Virtanen,¹Johanna M. U. Silvola,¹Anu Autio,¹Xiang-Guo Li,^2,3Heidi Liljenbäck,^1,4Sanna Hellberg,¹Riikka Siitonen,¹Mia Ståhle,¹Meeri Käkelä,¹Anu J. Airaksinen,³Kerttuli Helariutta,³and Tuula Tolvanen⁵ et al.

Academic Editor: Gaurav Malviya

Received27 Jul 2017

Accepted13 Nov 2017

Published31 Dec 2017

Abstract

Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a ligand of inflammation-inducible vascular adhesion protein-1 (VAP-1). We compared ⁶⁸Ga-DOTA- and ¹⁸F-fluorodeoxyribose- (FDR-) labeled Siglec-9 motif peptides for PET imaging of inflammation. Methods. Firstly, we examined ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-FDR-Siglec-9 in rats with skin/muscle inflammation. We then studied ¹⁸F-FDR-Siglec-9 for the detection of inflamed atherosclerotic plaques in mice and compared it with previous ⁶⁸Ga-DOTA-Siglec-9 results. Lastly, we estimated human radiation dosimetry from the rat data. Results. In rats, ⁶⁸Ga-DOTA-Siglec-9 (SUV, ) and ¹⁸F-FDR-Siglec-9 (SUV, ) showed comparable () imaging of inflammation. In atherosclerotic mice, ¹⁸F-FDR-Siglec-9 detected inflamed plaques with a target-to-background ratio () similar to previously tested ⁶⁸Ga-DOTA-Siglec-9 (). Human effective dose estimates for ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-FDR-Siglec-9 were 0.024 and 0.022 mSv/MBq, respectively. Conclusion. Both tracers are suitable for PET imaging of inflammation. The easier production and lower cost of ⁶⁸Ga-DOTA-Siglec-9 present advantages over ¹⁸F-FDR-Siglec-9, indicating it as a primary choice for clinical studies.

1. Introduction

Inflammation plays role in several diseases, such as, rheumatoid arthritis, diabetes and atherosclerosis. The early detection of inflammatory foci is critical for the adequate treatment of patients, and quantitative PET imaging may provide a valuable tool for diagnosis and monitoring of the effects of therapeutic interventions. ¹⁸F-FDG is the gold standard for PET, but not specific to inflammation. In addition, the high physiological accumulation of ¹⁸F-FDG in heart and brain makes it difficult to detect inflammatory foci close to these organs [1].

Vascular adhesion protein-1 (VAP-1) is an endothelial adhesion molecule, which is involved in leukocyte transendothelial migration from blood into the sites of inflammation. During inflammation VAP-1 translocates from intracellular storages on the endothelial cell surface where it contributes leukocyte-endothelial adhesion. Although VAP-1 plays important role in early phases of inflammation, its luminal expression on the endothelium will remain constant if the inflammation continues, which suggest VAP-1 as a promising target for both anti-inflammatory therapy and molecular imaging of inflammation [2]. The role of VAP-1 in atherosclerotic inflammation is unclear. VAP-1 expression is upregulated in atherosclerotic plaques in human carotid arteries [3, 4] and in the aorta of hypercholesterolemic rabbits [5]. VAP-1 is also expressed in soluble form (sVAP-1), which associates with atherosclerosis [6, 7].

We previously showed that sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a VAP-1 ligand, and the radiolabeled peptide (CARLSLSWRGLTLCPSK) containing residues 283–297 from Siglec-9 can be used for PET imaging of inflammation [4, 8–11].

In this study, we examined the detection of skin/muscle inflammation in rats, comparing the utility of the Siglec-9 motif peptides ⁶⁸Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid-conjugated ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-labeled fluorodeoxyribose-conjugated ¹⁸F-FDR-Siglec-9 [9]. We also examined ¹⁸F-FDR-Siglec-9 uptake in inflamed atherosclerotic plaques of mice and compared it with previous ⁶⁸Ga-DOTA-Siglec-9 results [4]. Finally, we used the rat PET data to estimate the human radiation doses for ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-FDR-Siglec-9.

2. Materials and Methods

2.1. Radiochemistry

⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-FDR-Siglec-9 were produced as previously described [8, 9].

2.2. Animal Models

Twenty-four hours before the PET studies, Sprague-Dawley rats (weight, g; ) were subcutaneously injected with turpentine oil (Sigma-Aldrich) to induce focal acute, sterile inflammation [12]. Before the injection, rats were shaved on the both forelegs. Inflamed area on the left foreleg contained both skin and muscle. The intact, contralateral side (right foreleg) was used as a control.

Six-month-old atherosclerotic low-density lipoprotein receptor-deficient mice (weight, g; ) expressing only apolipoprotein B100 (LDLR^−/−ApoB^100/100, strain #003000; Jackson Laboratory, Bar Harbor, ME, USA) were fed for 4 months with a Western-type diet [13]. Two-month-old C57BL/6N mice (weight, g; ) fed with a regular chow served as controls.

All animal experiments (Table 1) were approved by the national Animal Experiment Board in Finland and carried out in compliance with the EU directive.

2.3. Rat Studies

Rats were divided into two groups with Group 1 being intravenously (i.v.) given ⁶⁸Ga-DOTA-Siglec-9 ( MBq, ) and Group 2 ¹⁸F-FDR-Siglec-9 ( MBq, ). A 60 min dynamic PET acquisition was performed on a High Resolution Research Tomograph (HRRT; Siemens Medical Solutions, Knoxville, TN, USA). The PET data were reconstructed into 5 × 60 s and 11 × 300 s frames using an ordered-subsets expectation maximization 3D algorithm (OSEM3D). Quantitative PET image analysis was performed by defining regions of interest (ROIs) within the inflamed area (on the left foreleg), control area (on the right foreleg), kidneys, lungs, heart, liver, and urinary bladder using Carimas 2.8 software (Turku PET Centre). Results were expressed as standardized uptake values (SUV) and time-activity curves. SUV was calculated as a ratio of tissue radioactivity concentration (Bq/mL) and given radioactivity dose (Bq) divided by animal’s body weight.

After PET imaging, rats were sacrificed and various tissues were excised and weighed, and their radioactivity levels were measured with a gamma counter (1480 Wizard 3′′, PerkinElmer, Turku, Finland). The ex vivo biodistribution results were expressed as a percentage of the injected radioactivity dose per gram of tissue (% ID/g) and target-to-background ratio.

The inflamed area and control area tissue samples were frozen, cut into sections, and stained with hematoxylin-eosin (H&E) for morphological evaluation.

Absorbed doses of ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-FDR-Siglec-9 were calculated with the OLINDA/EXM version 1.0 software (organ level internal dose assessment and exponential modeling; Vanderbilt University, Nashville, TN, USA), which applies the MIRD schema (developed by the Medical Internal Radiation Dose committee of the Society of Nuclear Medicine) for radiation dose calculations in internal exposure. The software includes radionuclide information and selection of human body phantoms. The residence times derived from the rat data were integrated as the area under the time-activity curve. The residence times were converted into corresponding human values by multiplication with a factor to scale the organ and body weights: (), where and are the body weights of rat and human (a 70-kg male), respectively; and and are the organ weights of rat and human (organ weights for a 70 kg male), respectively [14].

2.4. Mouse Studies

To detect luminal expression of VAP-1, mice were intravenously (i.v.) injected with a monoclonal rat anti-mouse VAP-1 antibody (7–88, 1 mg/kg diluted in saline) [15] 10 min before sacrifice. Aorta samples were frozen and cut into 8 μm longitudinal sections, incubated for 30 min at room temperature in the dark with a secondary goat anti-rat antibody (working dilution, 5 μg/mL in phosphate-buffered saline (PBS) containing 5% normal mouse or human AB serum), conjugated to a fluorescent dye (Alexa Fluor 488; Invitrogen, Eugene, OR, USA), and rinsed twice in PBS for 5 min.

In PET studies, mice (19 atherosclerotic, 13 controls) were injected with MBq of ¹⁸F-FDR-Siglec-9. Twenty-five minutes after ¹⁸F-FDR-Siglec-9 injection, blood was drawn by cardiac puncture and the animals were killed. The thoracic aorta was excised and rinsed in saline to remove the blood. In addition, various other tissues were excised and patted dry. Samples of blood and urine were collected, and blood plasma was separated by centrifugation. All tissue samples were weighed, and their radioactivity levels were measured with a gamma counter (Triathler 3′′, Hidex Oy, Turku, Finland). The results were expressed as % ID/g and target-to-background ratio.

Autoradiography was used to study the distribution of radioactivity in the aorta in more detail, as described previously [13]. After careful superimposition of the autoradiographs and H&E stained images, the count densities of 540 ROIs (185: plaques, 241: normal vessel walls, and 114: adventitia) were analyzed using Tina 2.1 software. The autoradiography results were calculated as the photostimulated luminescence per unit area (PSL/mm²) normalized for injected radioactivity dose, and as ratios between the atherosclerotic plaque, normal vessel wall, and adventitia.

A subset of mice (two atherosclerotic, two controls) were injected with MBq of ¹⁸F-FDR-Siglec-9 and imaged with an Inveon Multimodality PET/CT (Siemens, Medical Solutions, Knoxville, TN, USA). Dynamic PET images were acquired for 60 min, followed by CT with a contrast agent (eXIATM160XL, Binitio Biomedical Inc., Ottawa, ON, Canada). The PET images were reconstructed with OSEM3D (frames 5 × 60 s, 3 × 300 s, 1 × 600 s, 2 × 1800 s).

Quantitative PET image analysis was performed by defining ROIs in the heart left ventricle (blood pool) and aortic arch as identified on the basis of the CT angiography by using the Inveon Research Workplace software (Siemens Medical Solutions, Knoxville, TN, USA). Time frames 10–20 min after injection were used for PET quantification, as previously reported in the same mouse model using ⁶⁸Ga-DOTA-Siglec-9 [4]. The results within ROIs were expressed as SUV and target-to-background ratio ().

Finally, we compared ¹⁸F-FDR-Siglec-9 results with previously reported ⁶⁸Ga-DOTA-Siglec-9 [4].

2.5. Statistical Analyses

All results are expressed as mean ± SD. Paired 2-tailed Student’s -tests were applied for intra-animal comparisons. Nonpaired data were compared between two groups using -tests and between multiple groups using ANOVA with Tukey’s correction. A value less than 0.05 was considered statistically significant.

3. Results

3.1. Radiochemistry

The specific radioactivity of ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-FDR-Siglec-9 was MBq/nmol and MBq/nmol, respectively, with radiochemical purity being >95% throughout the study.

3.2. Rat Studies

The turpentine oil caused focal soft-tissue inflammation with edema and leukocyte infiltration, predominantly neutrophils (Figure 1), and luminal VAP-1 as previously reported [8, 16].

The inflammatory focus was clearly visualized with both of the PET tracers and was demonstrated in the time-activity curves of the inflamed area, with the uptake kinetics of both tracers being comparable (Figure 2). In the inflamed area, the of ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-FDR-Siglec-9 was and , respectively (). The corresponding values for ⁶⁸Ga-DOTA-Siglec-9 () and ¹⁸F-FDR-Siglec-9 () were also close to each other (). Both tracers peaked about 10 min after the i.v. bolus injection, with a slow decrease thereafter. The inflammation-to-blood of ⁶⁸Ga-DOTA-Siglec-9 () and ¹⁸F-FDR-Siglec-9 () were also comparable (). Uptake in the heart, liver, kidneys, and urinary bladder was clearly visible with both tracers (Figure 2).

(a)

(b)

(c)

Ex vivo gamma counting at 60 min after injection demonstrated that ¹⁸F-FDR-Siglec-9 uptake was significantly higher than ⁶⁸Ga-DOTA-Siglec-9 uptake in several organs, including inflamed and control areas. The difference was particularly notable in the liver, pancreas, heart, and kidneys (Table 2). Only in the spleen was the uptake of ⁶⁸Ga-DOTA-Siglec-9 significantly higher than that of ¹⁸F-FDR-Siglec-9. Although the uptake of ¹⁸F-FDR-Siglec-9 in inflamed area ( % ID/g) was significantly higher () than that of ⁶⁸Ga-DOTA-Siglec-9 ( % ID/g), the inflammation-to-blood and inflamed-to-control area ratios (¹⁸F-FDR-Siglec-9: and ; ⁶⁸Ga-DOTA-Siglec-9: and ) were similar ( and , resp.).

Extrapolation from the rat PET data suggested estimated human effective doses for a 70 kg man of mSv/MBq for ⁶⁸Ga-DOTA-Siglec-9, and mSv/MBq for ¹⁸F-FDR-Siglec-9. The most critical organs were the urinary bladder wall with ⁶⁸Ga-DOTA-Siglec-9 ( mSv/MBq) and kidneys with ¹⁸F-FDR-Siglec-9 ( mSv/MBq) (Tables 3 and 4).

3.3. Mouse Studies

The LDLR^−/−ApoB^100/100 mice demonstrated atherosclerotic plaques, especially in the aortic arch, while the C57BL/6N mice showed no evidence of atherosclerosis. Furthermore, the LDLR^−/−ApoB^100/100 atherosclerotic lesions were VAP-1 positive, whereas normal vessel walls in the aortas of C57BL/6N mice were VAP-1-negative (Figure 3).

(a)

(b)

¹⁸F-FDR-Siglec-9 PET/CT imaging of atherosclerotic mice showed plaques in the aortic arch, with a target-to-background ratio of at 10–20 min after injection (Figure 4(a)). This ratio was similar to that reported previously for ⁶⁸Ga-DOTA-Siglec-9 (, ).

Figure 4

(a) The ¹⁸F-FDR-Siglec-9 PET/CT detects atherosclerotic plaques in the aortic root with a target-to-background ratio () of 1.6. The blood radioactivity concentration was determined from heart left ventricle using contrast-enhanced CT as anatomical reference. Arrow shows calcified atherosclerotic plaques in the aortic arch (a). (b) Ex vivo biodistribution of ¹⁸F-FDR-Siglec-9 in LDLR^−/−ApoB^100/100 and C57BL/N6 mice. (c) Quantification of ¹⁸F-FDR-Siglec-9 binding on the autoradiography of atherosclerotic mice aortas (, P values one-way ANOVA with Tukey’s correction). (d) Representative hematoxylin-eosin staining of a longitudinally sectioned LDLR^−/−ApoB^100/100 mouse aorta and (e) a superimposed autoradiograph (red lines represent the borders of the hematoxylin-eosin image). R1 and R2 are regions of interest in the plaque (excluding the media), R3 is in normal vessel wall (no lesion formation), and R4 is in adventitia (mainly adipose tissue around the aorta). (f) Hematoxylin-eosin staining of a longitudinally sectioned healthy C57BL/6N control mouse aorta. (g) Superimposed autoradiograph and hematoxylin-eosin staining (the black line represents the borders of the hematoxylin-eosin image). A: arch; AA: ascending aorta; B: brachiocephalic artery; LC: left common carotid artery; and LS: left subclavian artery. PSL/mm² = photostimulated luminescence/mm² normalized for injected radioactivity dose.

According to ex vivo gamma counting, the aortic uptake of ¹⁸F-FDR-Siglec-9 was significantly higher () in the LDLR^−/−ApoB^100/100 mice ( % ID/g) than in the C57BL/6N mice ( % ID/g; Table 5) and comparable to the uptake of ⁶⁸Ga-DOTA-Siglec-9 ( % ID/g, ).

Autoradiography of aortic cryosections further confirmed ¹⁸F-FDR-Siglec-9 accumulation in atherosclerotic plaques, with a plaque-to-healthy vessel wall ratio of () and plaque-to-adventitia ratio of (). In control mice, the uptake of ¹⁸F-FDR-Siglec-9 in healthy vessel wall was similar to that in the atherosclerotic mice (Figure 4). However, the plaque-to-healthy vessel wall ratios were higher with ⁶⁸Ga-DOTA-Siglec-9 () than with ¹⁸F-FDR-Siglec-9 ().

4. Discussion

VAP-1 targeted ligands are promising tools for PET imaging of inflammation. In this study, we compared the VAP-1 targeting tracers ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-FDR-Siglec-9 in the detection of experimental inflammation in rats and mice and also estimated the radiation burden to humans. We found that the uptake of both tracers was higher in skin/muscle inflammation than in healthy muscle, and in atherosclerotic rather than in nonatherosclerotic arterial walls. Both tracers resulted in a low radiation exposure, but the lower-cost and more straightforward radiolabeling procedures support the potential use of ⁶⁸Ga-DOTA-Siglec-9 for PET imaging of patients with inflammation.

The tested tracers have a similar amino acid sequence but a differently conjugated peptide structure (⁶⁸Ga-DOTA versus ¹⁸F-FDR). We hypothesized that the ¹⁸F-labeled tracer would provide improved visualization of inflammatory foci because it has a lower positron range (0.27 mm) than ⁶⁸Ga (1.05 mm). For PET imaging, ¹⁸F ( = 110 min, = 640 keV, ) is an ideal radionuclide, providing a high spatial resolution in the resulting images. ⁶⁸Ga ( = 68 min, keV, ) is a positron-emitting radiometal that is particularly suitable for the labeling of chelate-conjugated peptides. While production of ¹⁸F requires a cyclotron, ⁶⁸Ga is produced with an easily accessible low-cost ⁶⁸Ge/⁶⁸Ga-generator [17].

Although the inflammation detection characteristics of ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-FDR-Siglec-9 were similar, the uptake of ¹⁸F-FDR-Siglec-9 was higher in several nontarget tissues, including the control area. We do not have a clear explanation for the distinctive distribution patterns, particularly in the liver, pancreas, heart, and kidneys, but suspect that they were at least partly due to the sugar moiety. Similar results have been observed with ⁶⁸Ga-DOTANOC and ¹⁸F-FDR-NOC [18]. ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-FDR-Siglec-9 showed comparable in vivo imaging of inflammation in the rat model. The difference in the control area between the two tracers might at least partly be explained by the higher blood pool radioactivity of ¹⁸F-FDR-Siglec-9. Although both ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-FDR-Siglec-9 clearly delineated inflamed area by in vivo PET, the ¹⁸F-FDG uptake was higher ( at 90 min after injection) as reported in our previous rat studies with turpentine-induced inflammation [16].

As we earlier reported, the LDLR^−/−ApoB^100/100 mice expressed VAP-1 on endothelial cells lining the inflamed atherosclerotic lesions, while normal vessel walls in the aortas of C57BL/6N mice were VAP-1-negative [4]. In atherosclerotic mice, the aortic uptake of ¹⁸F-FDR-Siglec-9 was comparable to the previously reported uptake of ⁶⁸Ga-DOTA-Siglec-9 [4]. With both tracers, the atherosclerotic lesions in mice were best detectable by in vivo PET/CT imaging at 10–20 min after injection. Autoradiography revealed that the plaque-to-healthy vessel wall ratios were slightly higher with ⁶⁸Ga-DOTA-Siglec-9 than with ¹⁸F-FDR-Siglec-9, although both were close to the previously reported ratio for ¹⁸F-FDG () in a LDLR^−/−ApoB^100/100 model [13].

In general, in vivo PET imaging of such a small target as atherosclerotic lesion in mice aorta is very challenging. When size of the imaged structures is smaller than the spatial resolution of the scanner, spillover from adjacent tissues and partial volume effect may invalidate the quantification of PET data in addition to cardiac and respiratory movement artifacts. Although small-animal PET/CT image of atherosclerotic mouse showed hot spot in the lesion-rich aortic arch (Figure 4(a)), the ex vivo biodistribution showed that uptake in the whole thoracic aorta was much lower than the blood level (Figure 4(b)). Therefore, it is possible that the PET/CT imaging of atherosclerotic lesions is interfered with blood pool radioactivity. On the contrary, in the rat model, the size and location of focal skin/muscle inflammation as well as the blood radioactivity concentration were much more favorable for reliable PET imaging of inflamed area. The PET scanning protocols and quantification methods used in this study were based on our previous research to allow direct comparison of new and already existing results.

Extrapolated from rat PET data, the human radiation dose estimates for both ⁶⁸Ga-DOTA-Siglec-9 ( mSv/MBq) and ¹⁸F-FDR-Siglec-9 ( mSv/MBq) were similar to those for other ⁶⁸Ga-labeled tracers (e.g., ⁶⁸Ga-DOTANOC, 0.025 mSv/MBq) or ¹⁸F-FDG (0.019 mSv/MBq) [19, 20].

5. Conclusion

VAP-1 targeted ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-FDR-Siglec-9 peptides are potential tracers for the PET imaging of inflammation. The human radiation dose estimates indicate a low radiation exposure with either of the investigated tracers. The present study further strengthens the concept of a VAP-1-based imaging strategy for the in vivo detection of inflammation by PET.

Conflicts of Interest

Sirpa Jalkanen owns stocks in Faron Pharmaceuticals Ltd. The remaining authors have no conflicts of interest to disclose.

Acknowledgments

The authors thank Erica Nyman, Marja-Riitta Kajaala, Liisa Lempiäinen, Aake Honkaniemi, Timo Kattelus, and Sari Mäki for technical assistance. This research was conducted within the Finnish Centre of Excellence in Cardiovascular and Metabolic Diseases supported by the Academy of Finland, University of Turku, Turku University Hospital, and Åbo Akademi University. The research leading to these results was further supported by funding from the Academy of Finland (no. 258814), the State Research Funding (no. 13856), the Finnish Foundation for Cardiovascular Research, and the Sigrid Jusélius Foundation.

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Copyright © 2017 Helena Virtanen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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