Myra Kordos

18F-FDG Cell Labeling May Underestimate Transplanted Cell Homing: More Accurate, Efficient, and Stable Cell Labeling with Hexadecyl-4-[18F]Fluorobenzoate for in Vivo Tracking of Transplanted Human Progenitor Cells by Positron Emission Tomography:

Cell therapy is expected to restore perfusion and improve function in the ischemic/infarcted myocardium; however, the biological mechanisms and local effects of transplanted cells remain unclear. To assess cell fate in vivo, hexadecyl-4-[18F]fluorobenzoate (18F-HFB) cell labeling was evaluated for tracking human circulating progenitor cells (CPCs) with positron emission tomography (PET) and was compared to the commonly used 2-[18F]fluoro-2-deoxy-d-glucose (18F-FDG) labeling method in a rat myocardial infarction model. CPCs were labeled with 18F-HFB or 18F-FDG ex vivo under the same conditions. 18F-HFB cell-labeling efficiency (23.4 ± 7.5%) and stability (4 h, 88.4 ± 6.0%) were superior to 18F-FDG (7.6 ± 4.1% and 26.6 ± 6.1%, respectively; p < 0.05). Neither labeling approach significantly altered cell viability, phenotype or migration potential up to 24 h postlabeling. Two weeks after left anterior descending coronary artery ligation, rats received echo-guided intramyocardial injection in the infarct border zone with 18F-HFB-CPCs, 18F-FDG-CPCs, 18F-HFB, or 18F-FDG. Dynamic PET imaging of both 18F-HFB-CPCs and 18F-FDG-CPCs demonstrated that only 16–37% of the initial injection dose (ID) was retained in the injection site at 10 min postdelivery, and remaining activity fell significantly over the first 4 h posttransplantation. The 18F-HFB-CPC signal in the target area at 2 h (23.7 ± 14.7% ID/g) and 4 h (17.6 ± 13.3% ID/g) postinjection was greater than that of 18F-FDG-CPCs (5.4 ± 2.3% ID/g and 2.6 ± 0.7% ID/g, respectively; p < 0.05). Tissue biodistribution confirmed the higher radioactivity in the border zone of 18F-HFB-CPC rats. Immunostaining of heart tissue sections revealed no significant difference in cell retention between two labeled cell transplantation groups. Good correlation with biodistribution results was observed in the 18F-HFB-CPC rats (r = 0.81, p < 0.05). Compared to 18F-FDG, labeling human CPCs with 18F-HFB provides a more efficient, stable, and accurate way to quantify the distribution of transplanted cells. 18F-HFB cell labeling with PET imaging offers a better modality to enhance our understanding of early retention, homing, and engraftment with cardiac cell therapy.

Test–retest repeatability of quantitative cardiac 11C-meta-hydroxyephedrine measurements in rats by small animal positron emission tomography

INTRODUCTION The norepinephrine analogue (11)C-meta-hydroxyephedrine (HED) has been used to interrogate sympathetic neuronal reuptake in cardiovascular disease. Application for longitudinal studies in small animal models of disease necessitates an understanding of test-retest variability. This study evaluated the repeatability of multiple quantitative cardiac measurements of HED retention and washout and the pharmacological response to reuptake blockade and enhanced norepinephrine levels. METHODS Small animal PET images were acquired over 60 min following HED administration to healthy male Sprague Dawley rats. Paired test and retest scans were undertaken in individual animals over . Additional HED scans were conducted following administration of norepinephrine reuptake inhibitor desipramine or continuous infusion of exogenous norepinephrine. HED retention was quantified by retention index, standardized uptake value (SUV), monoexponential and one-compartment washout. Plasma and cardiac norepinephrine were measured by high performance liquid chromatography. RESULTS Test retest variability was lower for retention index (15% ± 12%) and SUV (19% ± 15%) as compared to monoexponential washout rates (21% ± 13%). Desipramine pretreatment reduced myocardial HED retention index by 69% and SUV by 85%. Chase treatment with desipramine increased monoexponential HED washout by 197% compared to untreated controls. Norepinephrine infusion dose-dependently reduced HED accumulation, reflected by both retention index and SUV, with a corresponding increase in monoexponential washout. Plasma and cardiac norepinephrine levels correlated with HED quantitative measurements. CONCLUSION The repeatability of HED retention index, SUV, and monoexponential washout supports its suitability for longitudinal PET studies in rats. Uptake and washout of HED are sensitive to acute increases in norepinephrine concentration.

PET imaging of a collagen matrix reveals its effective injection and targeted retention in a mouse model of myocardial infarction.

Injectable biomaterials have shown promise for cardiac regeneration therapy. However, little is known regarding their retention and distribution upon application in vivo. Matrix imaging would be useful for evaluating these important properties. Herein, hexadecyl-4-[(18)F]fluorobenzoate ((18)F-HFB) and Qdot labeling was used to evaluate collagen matrix delivery in a mouse model of myocardial infarction (MI). At 1 wk post-MI, mice received myocardial injections of (18)F-HFB- or Qdot-labeled matrix to assess its early retention and distribution (at 10 min and 2h) by positron emission tomography (PET), or fluorescence imaging, respectively. PET imaging showed that the bolus of matrix at 10 min redistributed evenly within the ischemic territory by 2h. Ex vivo biodistribution revealed myocardial matrix retention of ∼ 65%, which correlated with PET results, but may be an underestimate since (18)F-HFB matrix labeling efficiency was ∼ 82%. For covalently linked Qdots, labeling efficiency was ∼ 96%. Ex vivo Qdot quantification showed that ∼ 84% of the injected matrix was retained in the myocardium. Serial non-invasive PET imaging and validation by fluorescence imaging confirmed the effectiveness of the collagen matrix to be retained and redistributed within the infarcted myocardium. This study identifies matrix-targeted imaging as a promising modality for assessing the biodistribution of injectable biomaterials for application in the heart.

A three-dimensional model-based partial volume correction strategy for gated cardiac mouse PET imaging

Quantification in cardiac mouse positron emission tomography (PET) imaging is limited by the imaging spatial resolution. Spillover of left ventricle (LV) myocardial activity into adjacent organs results in partial volume (PV) losses leading to underestimation of myocardial activity. A PV correction method was developed to restore accuracy of the activity distribution for FDG mouse imaging. The PV correction model was based on convolving an LV image estimate with a 3D point spread function. The LV model was described regionally by a five-parameter profile including myocardial, background and blood activities which were separated into three compartments by the endocardial radius and myocardium wall thickness. The PV correction was tested with digital simulations and a physical 3D mouse LV phantom. In vivo cardiac FDG mouse PET imaging was also performed. Following imaging, the mice were sacrificed and the tracer biodistribution in the LV and liver tissue was measured using a gamma-counter. The PV correction algorithm improved recovery from 50% to within 5% of the truth for the simulated and measured phantom data and image uniformity by 5-13%. The PV correction algorithm improved the mean myocardial LV recovery from 0.56 (0.54) to 1.13 (1.10) without (with) scatter and attenuation corrections. The mean image uniformity was improved from 26% (26%) to 17% (16%) without (with) scatter and attenuation corrections applied. Scatter and attenuation corrections were not observed to significantly impact PV-corrected myocardial recovery or image uniformity. Image-based PV correction algorithm can increase the accuracy of PET image activity and improve the uniformity of the activity distribution in normal mice. The algorithm may be applied using different tracers, in transgenic models that affect myocardial uptake, or in different species provided there is sufficient image quality and similar contrast between the myocardium and surrounding structures.