TY - JOUR
T1 - Pharmacokinetics and microbiodistribution of 64Cu-labeled collagen-binding peptides in chronic myocardial infarction
AU - Kim, Heejung
AU - Lee, Sung Jin
AU - Kim, Jin Su
AU - Davies-Venn, Cynthia
AU - Cho, Hong Jun
AU - Won, Samuel J.
AU - Dejene, Eden
AU - Yao, Zhengsheng
AU - Kim, Insook
AU - Paik, Chang H.
AU - Bluemke, David A.
N1 - Funding Information:
This research was supported by the Intramural Research Program of Clinical Center, NIH and NCI contract no. HHSN261200800001E.
Publisher Copyright:
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - Objectives The aim of the study is to evaluate the pharmacokinetics and microbiodistribution of 64 Cu-labeled collagen-binding peptides. Methods The affinity constant (K D), association (k a), and dissociation rate constant (k d) for the peptide collagelin or its analog (named CRPA) binding to collagen were measured by biolayer interferometric analysis. Rats (n=4-5) with myocardial infarction or normal were injected intravenously with the 64 Cu-labeled peptides or 64 Cu-DOTA as a control. Dynamic PET imaging was performed for 60 min at 7-8 weeks after infarct. Fluorine-18 fluorodeoxyglucose PET imaging was performed to identify the viable myocardium. To validate the PET images, slices of heart samples from the base to the apex were analyzed using autoradiography and histology. Result The peptides bound to collagen with a K D of ∼0.9 μmol/l. The 64 Cu-peptides and 64 Cu-DOTA accumulated in the infarct area (confirmed by autoradiography and histology images) within 1 min of injection and were excreted rapidly through the renal system. The blood clearance curves were biphasic with elimination half-lives of 21.9±2.4, 26.2±4.6, and 21.2±2.1 min for 64 Cu-CRPA, 64 Cu-collagelin, and the control 64 Cu-DOTA, respectively. The clearance half-lives from the focal fibrotic tissue (24.1±1.5, 25.6±8.0, and 21.4±1.3 min, respectively) and remote myocardium (20.8±0.7, 21.0±5.5, and 19.1±2.4 min, respectively) were not significantly different. The uptake ratios of infarct-to-remote myocardium (1.93±0.18, 2.15±0.38, and 1.88±0.08, respectively) for 64 Cu-CRPA, 64 Cu-collagelin, and 64 Cu-DOTA remained stable for the time period between 10 and 60 min. Conclusion The distribution of the 64 Cu-collagelin probes corresponds to the heterogeneous distribution of expanded extracellular space in the setting of myocardial infarction. The overall washout rate from the fibrous tissue was determined by the slow washout rate (t 1/2 ≥20 min) of the peptides from the extracellular space to the vasculature, not by the dissociation rate (t 1/2 <2 min) of the 64 Cu-peptides from collagen.
AB - Objectives The aim of the study is to evaluate the pharmacokinetics and microbiodistribution of 64 Cu-labeled collagen-binding peptides. Methods The affinity constant (K D), association (k a), and dissociation rate constant (k d) for the peptide collagelin or its analog (named CRPA) binding to collagen were measured by biolayer interferometric analysis. Rats (n=4-5) with myocardial infarction or normal were injected intravenously with the 64 Cu-labeled peptides or 64 Cu-DOTA as a control. Dynamic PET imaging was performed for 60 min at 7-8 weeks after infarct. Fluorine-18 fluorodeoxyglucose PET imaging was performed to identify the viable myocardium. To validate the PET images, slices of heart samples from the base to the apex were analyzed using autoradiography and histology. Result The peptides bound to collagen with a K D of ∼0.9 μmol/l. The 64 Cu-peptides and 64 Cu-DOTA accumulated in the infarct area (confirmed by autoradiography and histology images) within 1 min of injection and were excreted rapidly through the renal system. The blood clearance curves were biphasic with elimination half-lives of 21.9±2.4, 26.2±4.6, and 21.2±2.1 min for 64 Cu-CRPA, 64 Cu-collagelin, and the control 64 Cu-DOTA, respectively. The clearance half-lives from the focal fibrotic tissue (24.1±1.5, 25.6±8.0, and 21.4±1.3 min, respectively) and remote myocardium (20.8±0.7, 21.0±5.5, and 19.1±2.4 min, respectively) were not significantly different. The uptake ratios of infarct-to-remote myocardium (1.93±0.18, 2.15±0.38, and 1.88±0.08, respectively) for 64 Cu-CRPA, 64 Cu-collagelin, and 64 Cu-DOTA remained stable for the time period between 10 and 60 min. Conclusion The distribution of the 64 Cu-collagelin probes corresponds to the heterogeneous distribution of expanded extracellular space in the setting of myocardial infarction. The overall washout rate from the fibrous tissue was determined by the slow washout rate (t 1/2 ≥20 min) of the peptides from the extracellular space to the vasculature, not by the dissociation rate (t 1/2 <2 min) of the 64 Cu-peptides from collagen.
KW - PET imaging
KW - collagen-specific peptides
KW - extracellular space fraction
KW - fibrosis
KW - myocardial infarction
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U2 - 10.1097/MNM.0000000000000590
DO - 10.1097/MNM.0000000000000590
M3 - Article
C2 - 27623511
AN - SCOPUS:84987642270
SN - 0143-3636
VL - 37
SP - 1306
EP - 1317
JO - Nuclear medicine communications
JF - Nuclear medicine communications
IS - 12
ER -