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1.
Basic Res Cardiol ; 116(1): 61, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34669013

RESUMO

Systemic effects of advanced cancer impact on the heart leading to cardiac atrophy and functional impairment. Using a murine melanoma cancer model (B16F10 melanoma cells stably transduced with a Ganciclovir (GCV)-inducible suicide gene), the present study analysed the recovery potential of cancer-induced cardiomyopathy with or without use of doxorubicin (Dox). After Dox-free tumor elimination and recovery for 70 ± 5 days, cancer-induced morphologic, functional, metabolic and molecular changes were largely reversible in mice previously bearing tumors. Moreover, grip strength and cardiac response to angiotensin II-induced high blood pressure were comparable with healthy control mice. In turn, addition of Dox (12 mg/kg BW) to melanoma-bearing mice reduced survival in the acute phase compared to GCV-alone induced recovery, while long-term effects on cardiac morphologic and functional recovery were similar. However, Dox treatment was associated with permanent changes in the cardiac gene expression pattern, especially the circadian rhythm pathway associated with the DNA damage repair system. Thus, the heart can recover from cancer-induced damage after chemotherapy-free tumor elimination. In contrast, treatment with the cardiotoxic drug Dox induces, besides well-known adverse acute effects, long-term subclinical changes in the heart, especially of circadian clock genes. Since the circadian clock is known to impact on cardiac repair mechanisms, these changes may render the heart more sensitive to additional stress during lifetime, which, at least in part, could contribute to late cardiac toxicity.

2.
Theranostics ; 11(16): 7755-7766, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335962

RESUMO

Background: Myocardial infarction (MI) evokes an organized remodeling process characterized by the activation and transdifferentiation of quiescent cardiac fibroblasts to generate a stable collagen rich scar. Early fibroblast activation may be amenable to targeted therapy, but is challenging to identify in vivo. We aimed to non-invasively image active fibrosis by targeting the fibroblast activation protein (FAP) expressed by activated (myo)fibroblasts, using a novel positron emission tomography (PET) radioligand [68Ga]MHLL1 after acute MI. Methods: One-step chemical synthesis and manual as well as module-based radiolabeling yielded [68Ga]MHLL1. Binding characteristics were evaluated in murine and human FAP-transfected cells, and stability tested in human serum. Biodistribution in healthy animals was interrogated by dynamic PET imaging, and metabolites were measured in blood and urine. The temporal pattern of FAP expression was determined by serial PET imaging at 7 d and 21 d after coronary artery ligation in mice as percent injected dose per gram (%ID/g). PET measurements were validated by ex vivo autoradiography and immunostaining for FAP and inflammatory macrophages. Results: [68Ga]MHLL1 displayed specific uptake in murine and human FAP-positive cells (p = 0.0208). In healthy mice the tracer exhibited favorable imaging characteristics, with low blood pool retention and dominantly renal clearance. At 7 d after coronary artery ligation, [68Ga]MHLL1 uptake was elevated in the infarct relative to the non-infarcted remote myocardium (1.3 ± 0.3 vs. 1.0 ± 0.2 %ID/g, p < 0.001) which persisted to 21 d after MI (1.3 ± 0.4 vs. 1.1 ± 0.4 %ID/g, p = 0.013). Excess unlabeled compound blocked tracer accumulation in both infarct and non-infarct remote myocardium regions (p < 0.001). Autoradiography and histology confirmed the regional uptake of [68Ga]MHLL1 in the infarct and especially border zone regions, as identified by Masson trichrome collagen staining. Immunostaining further delineated persistent FAP expression at 7 d and 21 d post-MI in the border zone, consistent with tracer distribution in vivo. Conclusion: The simplified synthesis of [68Ga]MHLL1 bears promise for non-invasive characterization of fibroblast activation protein early in remodeling after MI.


Assuntos
Endopeptidases/metabolismo , Radioisótopos de Gálio/farmacologia , Proteínas de Membrana/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Animais , Autorradiografia/métodos , Linhagem Celular Tumoral , Endopeptidases/fisiologia , Fibroblastos/metabolismo , Fibrose/diagnóstico por imagem , Radioisótopos de Gálio/metabolismo , Humanos , Masculino , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Imagem Molecular/métodos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Distribuição Tecidual/fisiologia , Tomografia Computadorizada por Raios X/métodos
3.
Theranostics ; 11(16): 7984-7994, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335975

RESUMO

Rationale: Acute myocardial infarction (MI) triggers a systemic inflammatory response including crosstalk along the heart-kidney axis. We employed radionuclide-based inflammation-targeted whole-body molecular imaging to identify potential cardio-renal crosstalk after MI in a translational setup. Methods: Serial whole-body positron emission tomography (PET) with the specific CXCR4 ligand 68Ga-Pentixafor was performed after MI in mice. Tracer retention in kidneys and heart was compared to hematopoietic organs to evaluate systemic inflammation, validated by ex vivo analysis and correlated with progressive contractile dysfunction. Additionally, 96 patients underwent 68Ga-Pentixafor PET within the first week after MI, for systems-based image analysis and to determine prognostic value for adverse renal outcome. Results: In mice, transient myocardial CXCR4 upregulation occurred early after MI. Cardiac and renal PET signal directly correlated over the time course (r = 0.62, p < 0.0001), suggesting an inflammatory link between organs. Ex-vivo autoradiography (r = 0.9, p < 0.01) and CD68 immunostaining indicated signal localization to inflammatory cell content. Renal signal at 7d was inversely proportional to left ventricular ejection fraction at 6 weeks after MI (r = -0.79, p < 0.01). In patients, renal CXCR4 signal also correlated with signal from infarct (r = 0.25, p < 0.05) and remote myocardium (r = 0.39, p < 0.0001). Glomerular filtration rate (GFR) was available in 48/96 (50%) during follow-up. Worsening of renal function (GFR loss >5 mL/min/1.73m2), occurred a mean 80.5 days after MI in 16/48 (33.3%). Kaplan-Meier analysis revealed adverse renal outcome for patients with elevated remote myocardial CXCR4 signal (p < 0.05). Multivariate Cox analysis confirmed an independent predictive value (relative to baseline GFR, LVEF, infarct size; HR, 5.27). Conclusion: Systems-based CXCR4-targeted molecular imaging identifies inflammatory crosstalk along the cardio-renal axis early after MI.


Assuntos
Coração/fisiopatologia , Rim/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Animais , Complexos de Coordenação/farmacologia , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Camundongos , Imagem Molecular/métodos , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Peptídeos Cíclicos/farmacologia , Tomografia por Emissão de Pósitrons/métodos , Receptores CXCR4/metabolismo , Volume Sistólico , Função Ventricular Esquerda , Remodelação Ventricular/fisiologia , Imagem Corporal Total/métodos
4.
Curr Cardiol Rep ; 23(8): 96, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196821

RESUMO

PURPOSE OF REVIEW: Current therapeutic strategies to mitigate heart failure progression after myocardial infarction involve support of endogenous repair through molecular targets. The capacity for repair varies greatly between individuals. In this review, we will assess how cardiac PET/CT enables precise characterization of early pathogenetic processes which govern ventricle remodeling and progression to heart failure. RECENT FINDINGS: Inflammation in the first days after myocardial infarction predicts subsequent functional decline and can influence therapy decisions. The expansion of anti-inflammatory approaches to improve outcomes after myocardial infarction may benefit from noninvasive characterization using imaging. Novel probes also allow visualization of fibroblast transdifferentiation and activation, as a precursor to ventricle remodeling. The expanding arsenal of molecular imaging agents in parallel with new treatment options provides opportunity to harmonize diagnostic imaging with precision therapy.


Assuntos
Infarto do Miocárdio , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Coração , Humanos , Imagem Molecular , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/terapia , Remodelação Ventricular
10.
Eur Heart J ; 41(37): 3564-3575, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32901270

RESUMO

AIMS: Balance between inflammatory and reparative leucocytes allows optimal healing after myocardial infarction (MI). Interindividual heterogeneity evokes variable functional outcome complicating targeted therapy. We aimed to characterize infarct chemokine CXC-motif receptor 4 (CXCR4) expression using positron emission tomography (PET) and establish its relationship to cardiac outcome. We tested whether image-guided early CXCR4 directed therapy attenuates chronic dysfunction. METHODS AND RESULTS: Mice (n = 180) underwent coronary ligation or sham surgery and serial PET imaging over 7 days. Infarct CXCR4 content was elevated over 3 days after MI compared with sham (%ID/g, Day 1:1.1 ± 0.2; Day 3:0.9 ± 0.2 vs. 0.6 ± 0.1, P < 0.001), confirmed by flow cytometry and histopathology. Mice that died of left ventricle (LV) rupture exhibited persistent inflammation at 3 days compared with survivors (1.2 ± 0.3 vs. 0.9 ± 0.2% ID/g, P < 0.001). Cardiac magnetic resonance measured cardiac function. Higher CXCR4 signal at 1 and 3 days independently predicted worse functional outcome at 6 weeks (rpartial = -0.4, P = 0.04). Mice were treated with CXCR4 blocker AMD3100 following the imaging timecourse. On-peak CXCR4 blockade at 3 days lowered LV rupture incidence vs. untreated MI (8% vs. 25%), and improved contractile function at 6 weeks (+24%, P = 0.01). Off-peak CXCR4 blockade at 7 days did not improve outcome. Flow cytometry analysis revealed lower LV neutrophil and Ly6Chigh monocyte content after on-peak treatment. Patients (n = 50) early after MI underwent CXCR4 PET imaging and functional assessment. Infarct CXCR4 expression in acute MI patients correlated with contractile function at time of PET and on follow-up. CONCLUSION: Positron emission tomography imaging identifies early CXCR4 up-regulation which predicts acute rupture and chronic contractile dysfunction. Imaging-guided CXCR4 inhibition accelerates inflammatory resolution and improves outcome. This supports a molecular imaging-based theranostic approach to guide therapy after MI.


Assuntos
Infarto do Miocárdio , Tomografia Computadorizada por Raios X , Animais , Humanos , Camundongos , Imagem Molecular , Miocárdio , Tomografia por Emissão de Pósitrons , Receptores CXCR4 , Remodelação Ventricular
11.
J Nucl Med ; 61(7): 951-961, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32303601

RESUMO

Radionuclide imaging of myocardial perfusion, function, and viability has been established for decades and remains a robust, evidence-based and broadly available means for clinical workup and therapeutic guidance in ischemic heart disease. Yet, powerful alternative modalities have emerged for this purpose, and their growth has resulted in increasing competition. But the potential of the tracer principle goes beyond the assessment of physiology and function, toward the interrogation of biology and molecular pathways. This is a unique selling point of radionuclide imaging, which has been underrecognized in cardiovascular medicine until recently. Now, molecular imaging methods for the detection of myocardial infiltration, device infection, and cardiovascular inflammation are successfully gaining clinical acceptance. This is further strengthened by the symbiotic quest of cardiac imaging and therapy for an increasing implementation of molecule-targeted procedures, in which specific therapeutic interventions require specific diagnostic guidance toward the most suitable candidates. This review will summarize the current advent of clinical cardiovascular molecular imaging and highlight its transformative contribution to the evolution of cardiovascular therapy beyond mechanical interventions and broad blockbuster medication, toward a future of novel, individualized molecule-targeted and molecular imaging-guided therapies.


Assuntos
Cardiologia , Doenças Cardiovasculares/diagnóstico por imagem , Imagem Molecular/métodos , Medicina Molecular , Medicina Nuclear , Humanos
12.
Eur J Nucl Med Mol Imaging ; 47(7): 1757-1768, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32125488

RESUMO

PURPOSE: Myocardial infarction (MI) triggers a local inflammatory response which orchestrates cardiac repair and contributes to concurrent neuroinflammation. Angiotensin-converting enzyme (ACE) inhibitor therapy not only attenuates cardiac remodeling by interfering with the neurohumoral system, but also influences acute leukocyte mobilization from hematopoietic reservoirs. Here, we seek to dissect the anti-inflammatory and anti-remodeling contributions of ACE inhibitors to the benefit of heart and brain outcomes after MI. METHODS: C57BL/6 mice underwent permanent coronary artery ligation (n = 41) or sham surgery (n = 9). Subgroups received ACE inhibitor enalapril (20 mg/kg, oral) either early (anti-inflammatory strategy; 10 days treatment beginning 3 days prior to surgery; n = 9) or delayed (anti-remodeling; continuous from 7 days post-MI; n = 16), or no therapy (n = 16). Cardiac and neuroinflammation were serially investigated using whole-body macrophage- and microglia-targeted translocator protein (TSPO) PET at 3 days, 7 days, and 8 weeks. In vivo PET signal was validated by autoradiography and histopathology. RESULTS: Myocardial infarction evoked higher TSPO signal in the infarct region at 3 days and 7 days compared with sham (p < 0.001), with concurrent elevation in brain TSPO signal (+ 18%, p = 0.005). At 8 weeks after MI, remote myocardium TSPO signal was increased, consistent with mitochondrial stress, and corresponding to recurrent neuroinflammation. Early enalapril treatment lowered the acute TSPO signal in the heart and brain by 55% (p < 0.001) and 14% (p = 0.045), respectively. The acute infarct signal predicted late functional outcome (r = 0.418, p = 0.038). Delayed enalapril treatment reduced chronic myocardial TSPO signal, consistent with alleviated mitochondrial stress. Early enalapril therapy tended to lower TSPO signal in the failing myocardium at 8 weeks after MI (p = 0.090) without an effect on chronic neuroinflammation. CONCLUSIONS: Whole-body TSPO PET identifies myocardial macrophage infiltration and neuroinflammation after MI, and altered cardiomyocyte mitochondrial density in chronic heart failure. Improved chronic cardiac outcome by enalapril treatment derives partially from acute anti-inflammatory activity with complementary benefits in later stages. Whereas early ACE inhibitor therapy lowers acute neuroinflammation, chronic alleviation is not achieved by early or delayed ACE inhibitor therapy, suggesting a more complex mechanism underlying recurrent neuroinflammation in ischemic heart failure.


Assuntos
Enalapril , Coração , Inflamação , Infarto do Miocárdio , Doenças do Sistema Nervoso , Doença Aguda , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Doença Crônica , Enalapril/farmacologia , Enalapril/uso terapêutico , Coração/diagnóstico por imagem , Coração/efeitos dos fármacos , Inflamação/diagnóstico por imagem , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/tratamento farmacológico , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/tratamento farmacológico
15.
J Nucl Cardiol ; 27(4): 1317-1327, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31044402

RESUMO

BACKGROUND: Quantitative cardiac contractile function assessment is the primary indicator of disease progression and therapeutic efficacy in small animals. Operator dependency is a major challenge with commonly used echocardiography. Simultaneous assessment of cardiac perfusion and function in nuclear scans would reduce burden on the animal and facilitate longitudinal studies. We evaluated the accuracy of contractile function measurements obtained from electrocardiogram-gated nuclear perfusion imaging compared with anatomic imaging. METHODS AND RESULTS: In healthy C57Bl/6N mice (n = 11), 99mTc-sestamibi SPECT and 13N-ammonia PET underestimated left ventricular volumes (23 to 28%, P = 0.02) compared to matched anatomic images, though ejection fraction (LVEF) was comparable (%, SPECT: 73 ± 8 vs CMR: 72 ± 6, P = 0.1). At 1 week after myocardial infarction (n = 13), LV volumes were significantly lower in perfusion images compared to CMR and contrast CT (P = 0.003), and LVEF was modestly overestimated (%, SPECT: 37 ± 8, vs CMR: 27 ± 7, P = 0.003). Nuclear images exhibited good intra- and inter-reader agreement. Perfusion SPECT accurately calculated infarct size compared to histology (r = 0.95, P < 0.001). CONCLUSIONS: Cardiac function can be calculated by gated nuclear perfusion imaging in healthy mice. After infarction, perfusion imaging overestimates LVEF, which should be considered for comparison to other modalities. Combined functional and infarct size analysis may optimize imaging protocols and reduce anaesthesia duration for longitudinal studies.

16.
JACC Cardiovasc Imaging ; 13(11): 2415-2429, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-31864993

RESUMO

As therapeutic approaches have evolved from exogenous bone marrow cell delivery to pharmacological stimulation of endogenous repair, so too has imaging of cardiac repair made significant strides forward. Evaluation of functional outcome remains a staple of noninvasive clinical imaging, which can robustly quantify contractile function, perfusion, and tissue viability. Direct labeling of cells or other novel therapeutics visualizes the whole-body distribution and pharmacokinetics of the therapeutic agent, providing insights into retention, targeting, and drug-tissue interactions. And finally, targeted molecular imaging agents are emerging that may be specifically coupled to drugs targeting the same pathway. This approach enables interrogation of temporal and spatial changes at the molecular level underlying tissue degeneration and regeneration, which facilitates accurate patient selection and timing for therapeutic intervention, as exemplified by recent efforts focusing on the role of inflammation in cardiac repair. The concept of image-guided repair carves out an important and evolving niche for molecular imaging in cardiovascular medicine, with the potential not only to predict outcomes but also to improve patient stratification and progress toward personalized reparative therapy.

17.
J Nucl Med ; 61(7): 977-980, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31806766

RESUMO

Acute myocardial infarction (MI) triggers a local and systemic inflammatory response. We recently showed microglia involvement using translocator protein imaging. Here, we evaluated whether 11C-methionine provides further insight into heart-brain inflammation networking. Methods: Male C57BL/6 mice underwent permanent coronary artery ligation followed by 11C-methionine PET at 3 and 7 d (n = 3). In subgroups, leukocyte homing was blocked by integrin antibodies (n = 5). The cellular substrate for PET signal was identified using brain section immunostaining. Results: 11C-methionine uptake (percentage injected dose/cm3) peaked in the MI region on day 3 (5.9 ± 0.9 vs. 2.4 ± 0.5), decreasing to the control level by day 7 (4.3 ± 0.6). Brain uptake was proportional to cardiac uptake (r = 0.47, P < 0.05), peaking also on day 3 (2.9 ± 0.4 vs. 2.4 ± 0.3) and returning to baseline on day 7 (2.3 ± 0.4). Integrin blockade reduced uptake at every time point. Immunostaining on day 3 revealed colocalization of the l-type amino acid transporter, with glial fibrillary acidic protein-positive astrocytes but not CD68-positive microglia. Conclusion: PET imaging with 11C-methionine specifically identifies an astrocyte component, enabling further dissection of the heart-brain axis in post-MI inflammation.


Assuntos
Astrócitos/patologia , Radioisótopos de Carbono , Encefalite/complicações , Metionina , Microglia/patologia , Infarto do Miocárdio/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Doença Aguda , Animais , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Imagem Corporal Total
18.
J Nucl Med ; 61(4): 590-596, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31653713

RESUMO

Inflammation contributes to ventricular remodeling after myocardial ischemia, but its role in nonischemic heart failure is poorly understood. Local tissue inflammation is difficult to assess serially during pathogenesis. Although 18F-FDG accumulates in inflammatory leukocytes and thus may identify inflammation in the myocardial microenvironment, it remains unclear whether this imaging technique can isolate diffuse leukocytes in pressure-overload heart failure. We aimed to evaluate whether inflammation with 18F-FDG can be serially imaged in the early stages of pressure-overload-induced heart failure and to compare the time course with functional impairment assessed by cardiac MRI. Methods: C57Bl6/N mice underwent transverse aortic constriction (TAC) (n = 22), sham surgery (n = 12), or coronary ligation as an inflammation-positive control (n = 5). MRI assessed ventricular geometry and contractile function at 2 and 8 d after TAC. Immunostaining identified the extent of inflammatory leukocyte infiltration early in pressure overload. 18F-FDG PET scans were acquired at 3 and 7 d after TAC, under ketamine-xylazine anesthesia to suppress cardiomyocyte glucose uptake. Results: Pressure overload evoked rapid left ventricular dilation compared with sham (end-systolic volume, day 2: 40.6 ± 10.2 µL vs. 23.8 ± 1.7 µL, P < 0.001). Contractile function was similarly impaired (ejection fraction, day 2: 40.9% ± 9.7% vs. 59.2% ± 4.4%, P < 0.001). The severity of contractile impairment was proportional to histology-defined myocardial macrophage density on day 8 (r = -0.669, P = 0.010). PET imaging identified significantly higher left ventricular 18F-FDG accumulation in TAC mice than in sham mice on day 3 (10.5 ± 4.1 percentage injected dose [%ID]/g vs. 3.8 ± 0.9 %ID/g, P < 0.001) and on day 7 (7.8 ± 3.7 %ID/g vs. 3.0 ± 0.8 %ID/g, P = 0.006), though the efficiency of cardiomyocyte suppression was variable among TAC mice. The 18F-FDG signal correlated with ejection fraction (r = -0.75, P = 0.01) and ventricular volume (r = 0.75, P < 0.01). Western immunoblotting demonstrated a 60% elevation of myocardial glucose transporter 4 expression in the left ventricle at 8 d after TAC, indicating altered glucose metabolism. Conclusion: TAC induces rapid changes in left ventricular geometry and contractile function, with a parallel modest infiltration of inflammatory macrophages. Metabolic remodeling overshadows inflammatory leukocyte signal using 18F-FDG PET imaging. More selective inflammatory tracers are requisite to identify the diffuse local inflammation in pressure overload.


Assuntos
Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Imagem Multimodal , Pressão/efeitos adversos , Remodelação Ventricular , Animais , Regulação da Expressão Gênica , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Inflamação/diagnóstico por imagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Miocárdica , Tomografia por Emissão de Pósitrons , Disfunção Ventricular Esquerda/complicações
19.
J Nucl Cardiol ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659697

RESUMO

BACKGROUND: Leukocyte subtypes bear distinct pro-inflammatory, reparative, and regulatory functions. Imaging inflammation provides information on disease prognosis and may guide therapy, but the cellular basis of the signal remains equivocal. We evaluated leukocyte subtype specificity of characterized clinically relevant inflammation-targeted radiotracers. METHODS AND RESULTS: Leukocyte populations were purified from blood- and THP-1-derived macrophages were polarized into M1-, reparative M2a-, or M2c-macrophages. In vitro uptake assays were conducted using tracers of enhanced glucose or amino acid metabolism and molecular markers of inflammatory cells. Both 18F-deoxyglucose (18F-FDG) and the labeled amino acid 11C-methionine (11C-MET) displayed higher uptake in neutrophils and monocytes compared to other leukocytes (P = 0.005), and markedly higher accumulation in pro-inflammatory M1-macrophages compared to reparative M2a-macrophages (P < 0.001). Molecular tracers 68Ga-DOTATATE targeting the somatostatin receptor type 2 and 68Ga-pentixafor targeting the chemokine receptor type 4 (CXCR4) exhibited broad uptake by leukocyte subpopulations and polarized macrophages with highest uptake in T-cells/natural killer cells and B-cells compared to neutrophils. Mitochondrial translocator protein (TSPO)-targeted 18F-flutriciclamide selectively accumulated in monocytes and pro-inflammatory M1 macrophages (P < 0.001). Uptake by myocytes and fibroblasts tended to be higher for metabolic radiotracers. CONCLUSIONS: The different in vitro cellular uptake profiles may allow isolation of distinct phases of the inflammatory pathway with specific inflammation-targeted radiotracers. The pathogenetic cell population in specific inflammatory diseases should be considered in the selection of an appropriate imaging agent.

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