A phase 1, first-in-human study of 18F-GP1 positron emission tomography for imaging acute arterial thrombosis

Sun Young Chae, Tae-Won Kwon, Soyoung Jin, Sun U Kwon, Changhwan Sung, Seung Jun Oh, Sang Ju Lee, Jungsu S Oh, Youngjin Han, Yong-Pil Cho, Narae Lee, Ji Young Kim, Norman Koglin, Mathias Berndt, Andrew W Stephens, Dae Hyuk Moon, Sun Young Chae, Tae-Won Kwon, Soyoung Jin, Sun U Kwon, Changhwan Sung, Seung Jun Oh, Sang Ju Lee, Jungsu S Oh, Youngjin Han, Yong-Pil Cho, Narae Lee, Ji Young Kim, Norman Koglin, Mathias Berndt, Andrew W Stephens, Dae Hyuk Moon

Abstract

Background: 18F-GP1 is a novel positron emission tomography (PET) tracer that targets glycoprotein IIb/IIIa receptors on activated platelets. The study objective was to explore the feasibility of directly imaging acute arterial thrombosis (AAT) with 18F-GP1 PET/computed tomography (PET/CT) and to quantitatively assess 18F-GP1 uptake. Safety, biodistribution, pharmacokinetics and metabolism were also evaluated.

Methods: Adult patients who had signs or symptoms of AAT or had recently undergone arterial intervention or surgery within 14 days prior to 18F-GP1 PET/CT were eligible for inclusion. The AAT focus was demonstrated by conventional imaging within the 5 days prior to 18F-GP1 administration. Whole-body dynamic 18F-GP1 PET/CT images were acquired for up to 140 min after injection of 250 MBq of 18F-GP1. Venous plasma samples were analysed to determine 18F-GP1 clearance and metabolite formation.

Results: Among the ten eligible patients assessed, underlying diseases were abdominal aortic aneurysm with endovascular repair (n = 6), bypass surgery and stent placement (n = 1), endarterectomy (n = 1), arterial dissection (n = 1) and acute cerebral infarction (n = 1). 18F-GP1 administration and PET/CT procedures were well tolerated, with no drug-related adverse events. All patients showed high initial 18F-GP1 uptake in the spleen, kidney and blood pool, followed by rapid clearance. Unmetabolised plasma 18F-GP1 levels peaked at 4 min post-injection and decreased over time until 120 min. The overall image quality was sufficient for diagnosis in all patients and AAT foci were detected in all participants. The 18F-GP1 uptake in AAT foci remained constant from 7 min after injection and began to separate from the blood pool after 20 min. The median standardised uptake value of AAT was 5.0 (range 2.4-7.9) at 120 min post-injection. The median ratio of standardised uptake value of AAT foci to the mean blood pool activity was 3.4 (range 2.0-6.3) at 120 min.

Conclusions: 18F-GP1 is a safe and promising novel PET tracer for imaging AAT with a favourable biodistribution and pharmacokinetic profile.

Trial registration: ClinicalTrials.gov identifier: NCT02864810 , Registered August 3, 2016.

Keywords: 18F-GP1; Arterial thrombosis; Glycoprotein IIb/IIIa receptor; Platelet activation; Positron emission tomography.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Ministry of Food and Drug Safety of Korea and the Asan Medical Center Institutional Review Board (2016-0138). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all participants included in the study.

Consent for publication

Not applicable.

Competing interests

DHM has received research grants from Life Molecular Imaging GmbH (formerly Piramal Imaging GmbH, Berlin, Germany). NK, MB and AWS are employees of Life Molecular Imaging GmbH, formerly Piramal Imaging GmbH, Berlin, Germany. The other authors declare that they have no conflicts of interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
18F-GP1 biodistribution over time. The 18F-GP1 uptake in the kidney, spleen and blood gradually decreases over time. The 18F-GP1 uptake in AAT lesions remains constant from 7 min after injection. The median values of ten patients are shown
Fig. 2
Fig. 2
18F-GP1 PET/CT and CT images of a 73-year-old man who had undergone endovascular abdominal aortic aneurysm repair surgery. Anterior maximum intensity projections of 18F-GP1 PET/CT show positive 18F-GP1 accumulation in the inner surface of abdominal aortic graft (arrow) and the lower portion of the left kidney (dotted arrow), which are increasingly distinct in later images as background 18F-GP1 activity clears over time via urinary and hepatobiliary excretion (a). Transaxial CT and PET images show increased 18F-GP1 uptake in the inner surface of the left iliac artery graft (b, arrows), but no 18F-GP1 uptake in the chronic intraluminal thrombus in the right iliac aneurysmal sac (b, arrow heads). Additional positive 18F-GP1 uptake is observed in the non-enhancing renal ischaemic area involving the lower portion of the left kidney (c, dotted arrows)
Fig. 3
Fig. 3
18F-GP1 PET/CT and magnetic resonance images of a 61-year-old man with acute cerebral infarction in the right middle cerebral artery territory and basal ganglia. Transaxial images of 18F-GP1 PET/CT at 60 min after injection show increased uptake in the petrous part of the right internal carotid artery (a, arrows) and right proximal internal carotid artery (b, dotted arrows). Magnetic resonance images reveal filling defects in right internal carotid artery (a, b). A smooth echogenic plaque was seen from the bilateral carotid bulbs to the proximal internal carotid arteries on transcranial Doppler (large-artery atherosclerosis subtype)
Fig. 4
Fig. 4
18F-GP1 PET/CT images of a 63-year-old man with right common femoral artery endarterectomy and right popliteal artery angioplasty. Anterior maximum intensity projection and transaxial images of 18F-GP1 PET/CT at 120 min after injection show a focal increased uptake in the right popliteal artery (a, b; arrows), which corresponds to the AAT lesion after angioplasty (c). Additional positive 18F-GP1 uptake is observed in the dissected right distal external iliac artery (d, e; dotted arrows) and right common femoral artery (a, f; arrow heads) where endarterectomy was performed due to occlusion 3 days before 18F-GP1 PET/CT (g, arrow head)

References

    1. Mackman N. Triggers, targets and treatments for thrombosis. Nature. 2008;451:914–918. doi: 10.1038/nature06797.
    1. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2012;380:2095–2128. doi: 10.1016/S0140-6736(12)61728-0.
    1. Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart disease and stroke Statistics-2018 update: a report from the American Heart Association. Circulation. 2018;137:e67–e492. doi: 10.1161/CIR.0000000000000558.
    1. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837–1847. doi: 10.1161/01.CIR.97.18.1837.
    1. Goff DC, Jr, Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Gibbons R, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation. 2014;129:S49–S73. doi: 10.1161/01.cir.0000437741.48606.98.
    1. Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008;358:1336–1345. doi: 10.1056/NEJMoa072100.
    1. Arbab-Zadeh A, Fuster V. The myth of the "vulnerable plaque": transitioning from a focus on individual lesions to atherosclerotic disease burden for coronary artery disease risk assessment. J Am Coll Cardiol. 2015;65:846–855. doi: 10.1016/j.jacc.2014.11.041.
    1. Fleg JL, Stone GW, Fayad ZA, Granada JF, Hatsukami TS, Kolodgie FD, et al. Detection of high-risk atherosclerotic plaque: report of the NHLBI working group on current status and future directions. JACC Cardiovasc Imaging. 2012;5:941–955. doi: 10.1016/j.jcmg.2012.07.007.
    1. Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364:226–235. doi: 10.1056/NEJMoa1002358.
    1. Calvert PA, Obaid DR, O'Sullivan M, Shapiro LM, McNab D, Densem CG, et al. Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VH-IVUS in vulnerable atherosclerosis) study. JACC Cardiovasc Imaging. 2011;4:894–901. doi: 10.1016/j.jcmg.2011.05.005.
    1. Cheng JM, Garcia-Garcia HM, de Boer SP, Kardys I, Heo JH, Akkerhuis KM, et al. In vivo detection of high-risk coronary plaques by radiofrequency intravascular ultrasound and cardiovascular outcome: results of the ATHEROREMO-IVUS study. Eur Heart J. 2014;35:639–647. doi: 10.1093/eurheartj/eht484.
    1. Saam T, Hetterich H, Hoffmann V, Yuan C, Dichgans M, Poppert H, et al. Meta-analysis and systematic review of the predictive value of carotid plaque hemorrhage on cerebrovascular events by magnetic resonance imaging. J Am Coll Cardiol. 2013;62:1081–1091. doi: 10.1016/j.jacc.2013.06.015.
    1. Adamson PD, Dweck MR, Newby DE. The vulnerable atherosclerotic plaque: in vivo identification and potential therapeutic avenues. Heart. 2015;101:1755–1766. doi: 10.1136/heartjnl-2014-307099.
    1. Stefanadis C, Antoniou CK, Tsiachris D, Pietri P. Coronary atherosclerotic vulnerable plaque: current perspectives. J Am Heart Assoc. 2017;6:e005543. doi: 10.1161/JAHA.117.005543.
    1. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: task force for the Management of Acute Coronary Syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC) Eur Heart J. 2016;37:267–315. doi: 10.1093/eurheartj/ehv320.
    1. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49:e46–e110. doi: 10.1161/STR.0000000000000158.
    1. Mehta SR, Granger CB, Boden WE, Steg PG, Bassand JP, Faxon DP, et al. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med. 2009;360:2165–2175. doi: 10.1056/NEJMoa0807986.
    1. Thiele H, Rach J, Klein N, Pfeiffer D, Hartmann A, Hambrecht R, et al. Optimal timing of invasive angiography in stable non-ST-elevation myocardial infarction: the Leipzig immediate versus early and late PercutaneouS coronary intervention triAl in NSTEMI (LIPSIA-NSTEMI trial) Eur Heart J. 2012;33:2035–2043. doi: 10.1093/eurheartj/ehr418.
    1. Bang OY, Lee PH, Joo SY, Lee JS, Joo IS, Huh K. Frequency and mechanisms of stroke recurrence after cryptogenic stroke. Ann Neurol. 2003;54:227–234. doi: 10.1002/ana.10644.
    1. Mazighi M, Labreuche J, Gongora-Rivera F, Duyckaerts C, Hauw JJ, Amarenco P. Autopsy prevalence of intracranial atherosclerosis in patients with fatal stroke. Stroke. 2008;39:1142–1147. doi: 10.1161/STROKEAHA.107.496513.
    1. Mazighi M, Labreuche J, Gongora-Rivera F, Duyckaerts C, Hauw JJ, Amarenco P. Autopsy prevalence of proximal extracranial atherosclerosis in patients with fatal stroke. Stroke. 2009;40:713–718. doi: 10.1161/STROKEAHA.108.514349.
    1. Kim J, Park JE, Nahrendorf M, Kim DE. Direct thrombus imaging in stroke. J Stroke. 2016;18:286–296. doi: 10.5853/jos.2016.00906.
    1. Hellings WE, Peeters W, Moll FL, Piers SR, van Setten J, Van der Spek PJ, et al. Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study. Circulation. 2010;121:1941–1950. doi: 10.1161/CIRCULATIONAHA.109.887497.
    1. Lohrke J, Siebeneicher H, Berger M, Reinhardt M, Berndt M, Mueller A, et al. 18F-GP1, a novel PET tracer designed for high-sensitivity, low-background detection of thrombi. J Nucl Med. 2017;58:1094–1099. doi: 10.2967/jnumed.116.188896.
    1. Kim C, Lee JS, Han Y, Chae SY, Jin S, Sung C, et al. Glycoprotein IIb/IIIa receptor imaging with (18)F-GP1 positron emission tomography for acute venous thromboembolism: an open-label, non-randomized, first-in-human phase 1 study. J Nucl Med. 2018; 10.2967/jnumed.118.212084.
    1. Pedrini L, Dondi M, Magagnoli A, Magnoni F, Pisano E, Del Giudice E, et al. Evaluation of thrombogenicity of fluoropassivated polyester patches following carotid endarterectomy. Ann Vasc Surg. 2001;15:679–683. doi: 10.1007/s100160010129.
    1. Heyligers JM, Verhagen HJ, Rotmans JI, Weeterings C, de Groot PG, Moll FL, et al. Heparin immobilization reduces thrombogenicity of small-caliber expanded polytetrafluoroethylene grafts. J Vasc Surg. 2006;43:587–591. doi: 10.1016/j.jvs.2005.10.038.
    1. van der Steenhoven TJ, Bosman WM, Tersteeg C, Jacobs MJ, Moll FL, de Groot PG, et al. Thrombogenicity of a new injectable biocompatible elastomer for aneurysm exclusion, compared to expanded polytetrafluoroethylene in a human ex vivo model. Eur J Vasc Endovasc Surg. 2012;43:675–680. doi: 10.1016/j.ejvs.2012.02.025.
    1. Tang D, Nickels ML, Tantawy MN, Buck JR, Manning HC. Preclinical imaging evaluation of novel TSPO-PET ligand 2-(5,7-Diethyl-2-(4-(2-[(18)F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)- N,N-diethylacetamide ([ (18)F]VUIIS1008) in glioma. Mol Imaging Biol. 2014;16:813–820. doi: 10.1007/s11307-014-0743-2.
    1. Mackie IJ, Kitchen S, Machin SJ, Lowe GD, Haemostasis, thrombosis task force of the British Committee for Standards in H Guidelines on fibrinogen assays. Br J Haematol. 2003;121:396–404. doi: 10.1046/j.1365-2141.2003.04256.x.
    1. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50(Suppl 1):122S–150S. doi: 10.2967/jnumed.108.057307.
    1. Ariyoshi H, Okuyama M, Okahara K, Kawasaki T, Kambayashi J, Sakon M, et al. Expanded polytetrafluoroethylene (ePTFE) vascular graft loses its thrombogenicity six months after implantation. Thromb Res. 1997;88:427–433. doi: 10.1016/S0049-3848(97)00278-8.
    1. Perini P, Massoni CB, Azzarone M, Ucci A, Rossi G, Gallitto E, et al. Title: significance and risk factors for Intraprosthetic mural thrombus in abdominal aortic endografts: a systematic review and meta-analysis. Ann Vasc Surg. 2018; 10.1016/j.avsg.2018.04.027.
    1. Cornelissen SA, Verhagen HJ, van Herwaarden JA, Vonken EJ, Moll FL, Bartels LW. Lack of thrombus organization in nonshrinking aneurysms years after endovascular abdominal aortic aneurysm repair. J Vasc Surg. 2012;56:938–942. doi: 10.1016/j.jvs.2012.03.015.
    1. Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev Cardiol. 2015;12:30–47. doi: 10.1038/nrcardio.2014.156.

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