Top

Molecular Imaging and Biology

Published in:

01-08-2011 | Research Article

Blood Clearance Kinetics, Biodistribution, and Radiation Dosimetry of a Kit-Formulated Integrin α_vβ₃-Selective Radiotracer ^99mTc-3PRGD₂ in Non-Human Primates

Authors: Bing Jia, Zhaofei Liu, Zhaohui Zhu, Jiyun Shi, Xiaona Jin, Huiyun Zhao, Fang Li, Shuang Liu, Fan Wang

Published in: Molecular Imaging and Biology | Issue 4/2011

Abstract

Purpose

^99mTc-3PRGD₂ is a ^99mTc-labeled dimeric cyclic RGD peptide with increased receptor binding affinity and improved kinetics for in vivo imaging of integrin α_vβ₃ expression in nude mouse model. To accelerate its clinical translation, we reported here the evaluation of the kit-formulated ^99mTc-3PRGD₂ in healthy cynomolgus primates for its blood clearance kinetics, biodistribution, and radiation dosimetry.

Procedures

Healthy cynomolgus primates (4.1 ± 0.7 kg, n = 5) were anesthetized, and the venous blood samples were collected via a femoral vein catheter at various time points after injection of ~555 MBq of ^99mTc-3PRGD₂. Serial whole-body scans were performed with a dual-head single photon emission computed tomography system after administering ~555 MBq of ^99mTc-3PRGD₂ in the non-human primates, and the radiation dosimetry estimate was calculated.

Results

^99mTc-3PRGD₂ could be easily obtained from freeze-dried kits with high radiochemical purity (>95%) and high specific activity (~5 Ci/μmol). ^99mTc-3PRGD₂ had a rapid blood clearance with less than 1% of the initial radioactivity remaining in the blood circulation at 60 min postinjection. No adverse reactions were observed up to 4 weeks after the repeated dosing. The whole-body images exhibited high kidney uptake of ^99mTc-3PRGD₂ and high radioactivity accumulation in the bladder, demonstrating the rapid renal clearance of this tracer. The highest radiation doses of ^99mTc-3PRGD₂ were found in the kidneys (13.2 ± 1.08 μGy/MBq) and the bladder wall (33.1 ± 1.91 μGy/MBq).

Conclusion

^99mTc-3PRGD₂ can be readily available using the kit formulation. This tracer is safe and well tolerated, and no adverse events occurred in non-human primates. Further clinical testing and translation of ^99mTc-3PRGD₂ for noninvasive imaging of integrin α_vβ₃ in humans are warranted.

Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:11–25PubMedCrossRef

Brooks PC, Clark RA, Cheresh DA (1994) Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science 264:569–571PubMedCrossRef

Cai W, Chen X (2008) Multimodality molecular imaging of tumor angiogenesis. J Nucl Med 49(Suppl 2):113S–128SPubMedCrossRef

Cai W, Niu G, Chen X (2008) Imaging of integrins as biomarkers for tumor angiogenesis. Curr Pharm Des 14:2943–2973PubMedCrossRef

Beer AJ, Haubner R, Sarbia M, Goebel M, Luderschmidt S, Grosu AL, Schnell O, Niemeyer M, Kessler H, Wester HJ et al (2006) Positron emission tomography using [¹⁸F]Galacto-RGD identifies the level of integrin α_vβ₃ expression in man. Clin Cancer Res 12:3942–3949PubMedCrossRef

Haubner R, Weber WA, Beer AJ, Vabuliene E, Reim D, Sarbia M, Becker KF, Goebel M, Hein R, Wester HJ et al (2005) Noninvasive visualization of the activated α_vβ₃ integrin in cancer patients by positron emission tomography and [¹⁸F]Galacto-RGD. PLoS Med 2:e70PubMedCrossRef

Kenny LM, Coombes RC, Oulie I, Contractor KB, Miller M, Spinks TJ, McParland B, Cohen PS, Hui AM, Palmieri C et al (2008) Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand ¹⁸F-AH111585 in breast cancer patients. J Nucl Med 49:879–886PubMedCrossRef

Wang L, Shi J, Kim YS, Zhai S, Jia B, Zhao H, Liu Z, Wang F, Chen X, Liu S (2009) Improving tumor-targeting capability and pharmacokinetics of ^99mTc-labeled cyclic RGD dimers with PEG₄ linkers. Mol Pharm 6:231–245PubMedCrossRef

Liu Z, Liu S, Wang F, Liu S, Chen X (2009) Noninvasive imaging of tumor integrin expression using ¹⁸F-labeled RGD dimer peptide with PEG₄ linkers. Eur J Nucl Med Mol Imaging 36:1296–1307PubMedCrossRef

10.

Liu Z, Niu G, Shi J, Liu S, Wang F, Liu S, Chen X (2009) ⁶⁸ Ga-labeled cyclic RGD dimers with Gly₃ and PEG₄ linkers: promising agents for tumor integrin α_vβ₃ PET imaging. Eur J Nucl Med Mol Imaging 36:947–957PubMedCrossRef

11.

Shi J, Kim YS, Zhai S, Liu Z, Chen X, Liu S (2009) Improving tumor uptake and pharmacokinetics of ⁶⁴Cu-labeled cyclic RGD peptide dimers with Gly₃ and PEG₄ linkers. Bioconjug Chem 20:750–759PubMedCrossRef

12.

Liu S (2009) Radiolabeled cyclic RGD peptides as integrin α_vβ₃-targeted radiotracers: maximizing binding affinity via bivalency. Bioconjugate Chem 20:2199–2213CrossRef

13.

Beer AJ, Haubner R, Wolf I, Goebel M, Luderschmidt S, Niemeyer M, Grosu AL, Martinez MJ, Wester HJ, Weber WA et al (2006) PET-based human dosimetry of [¹⁸F]Galacto-RGD, a new radiotracer for imaging α_vβ₃ expression. J Nucl Med 47:763–769PubMed

14.

Kowalsky RJ, Falen SW (2004) Radiopharmaceuticals in nuclear pharmacy and nuclear medicine, 2nd edn. American Pharmacist Association, Washington, D.C., pp 71–98

Title: Blood Clearance Kinetics, Biodistribution, and Radiation Dosimetry of a Kit-Formulated Integrin αvβ3-Selective Radiotracer 99mTc-3PRGD2 in Non-Human Primates
Authors: Bing Jia
Zhaofei Liu
Zhaohui Zhu
Jiyun Shi
Xiaona Jin
Huiyun Zhao
Fang Li
Shuang Liu
Fan Wang
Publication date: 01-08-2011
Publisher: Springer-Verlag
Published in: Molecular Imaging and Biology / Issue 4/2011
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-010-0385-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Blood Clearance Kinetics, Biodistribution, and Radiation Dosimetry of a Kit-Formulated Integrin α_vβ₃-Selective Radiotracer ^99mTc-3PRGD₂ in Non-Human Primates

Abstract

Purpose

Procedures

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Procedures

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 4/2011

Biodistribution and Radiation Dosimetry of the Glycine Transporter-1 Ligand 11C-GSK931145 Determined from Primate and Human Whole-Body PET

Localization of Deoxyglucose and Annexin A5 in Experimental Atheroma Correlates with Macrophage Infiltration but not Lipid Deposition in the Lesion

Preclinical Lymphatic Imaging

Biodistribution, Pharmacokinetics, and Nuclear Imaging Studies of 111In-labeled rGel/BLyS Fusion Toxin in SCID Mice Bearing B Cell Lymphoma

[11C]acetate PET/CT Visualizes Skeletal Muscle Exercise Participation, Impaired Function, and Recovery after Hip Arthroplasty; First Results

Characterization of the Inflammatory Response in a Photothrombotic Stroke Model by MRI: Implications for Stem Cell Transplantation