Pharmacokinetics and microbiodistribution of 64Cu-labeled collagen-binding peptides in chronic myocardial infarction.
OBJECTIVE
The aim of the study is to evaluate the pharmacokinetics and microbiodistribution of Cu-labeled collagen-binding peptides.


METHODS
The affinity constant (KD), association (ka), and dissociation rate constant (kd) 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 Cu-labeled peptides or 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.


RESULTS
The peptides bound to collagen with a KD of ∼0.9 µmol/l. The Cu-peptides and 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 Cu-CRPA, Cu-collagelin, and the control 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 Cu-CRPA, Cu-collagelin, and Cu-DOTA remained stable for the time period between 10 and 60 min.


CONCLUSIONS
The distribution of the 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 (t1/2≥20 min) of the peptides from the extracellular space to the vasculature, not by the dissociation rate (t1/2<2 min) of the Cu-peptides from collagen.
aRadiopharmaceutical Laboratory, Department of Radiology and Imaging Sciences, Clinical Center, Nuclear Medicine Division, National Institutes of Health, Bethesda bApplied and Developmental Research Directorate, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick, Maryland, USA cMolecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Heejung
H
Kim
Sung-Jin
SJ
Lee
Jin Su
JS
Kim
Cynthia
C
Davies-Venn
Hong-Jun
HJ
Cho
Samuel J
SJ
Won
Eden
E
Dejene
Zhengsheng
Z
Yao
Insook
I
Kim
Chang H
CH
Paik
David A
DA
Bluemke
D000818:Animals; D001345:Autoradiography; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism*; D003301:Copper Radioisotopes / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D006321:Heart / Q000000981:diagnostic imaging; D009203:Myocardial Infarction / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D014018:Tissue Distribution
D003301:Copper Radioisotopes; D010455:Peptides; D019275:Radiopharmaceuticals; D003094:Collagen