Effect of acute high-intensity interval exercise on a mouse model of doxorubicin-induced cardiotoxicity: a pilot study.

Background: It is unknown whether high-intensity interval exercise (HIIE) may potentiate or attenuate the cardiotoxic effect of chemotherapy agents such as doxorubicin (DOX) when performed shortly after treatment. The study aimed to investigate the effect of acute HIIE on cardiac function and structure performed either 1, 2 or 3 days after DOX injection in an animal model.

Methods: Female C57bl/6 mice (n = 28), 70 days old, received a bolus 20 mg/kg intravenous tail vein DOX injection.

Medicinal (Radio) Chemistry: Building Radiopharmaceuticals for the Future.

Radiopharmaceuticals are increasingly playing a leading role in diagnosing, monitoring, and treating disease. In comparison with conventional pharmaceuticals, the development of radiopharmaceuticals does follow the principles of medicinal chemistry in the context of imaging-altered physiological processes. The design of a novel radiopharmaceutical has several steps similar to conventional drug discovery and some particularity.

A Reliable Production System of Large Quantities of [N]Ammonia for Multiple Human Injections.

[N]Ammonia is one of the most commonly used Positron Emission Tomography (PET) radiotracers in humans to assess myocardial perfusion and measure myocardial blood flow. Here, we report a reliable semi-automated process to manufacture large quantities of [N]ammonia in high purity by proton-irradiation of a 10 mM aqueous ethanol solution using an in-target process under aseptic conditions. Our simplified production system is based on two syringe driver units and an in-line anion-exchange purification for up to three consecutive productions of ~30 GBq (~800 mCi) (radiochemical yield = 69 ± 3% n.

[ F]Fluoropyridine-losartan: A new approach toward human Positron Emission Tomography imaging of Angiotensin II Type 1 receptors.

Angiotensin II type 1 receptors (AT R) blocker losartan is used in patients with renal and cardiovascular diseases. [ F]fluoropyridine-losartan has shown favorable binding profile for quantitative renal PET imaging of AT R with selective binding in rats and pigs, low interference of radiometabolites and appropriate dosimetry for clinical translation. A new approach was developed to produce [ F]fluoropyridine-losartan in very high molar activity.

Performance of an integrated multimodality image guidance and dose-planning system supporting tumor-targeted HDR brachytherapy for prostate cancer.

Background And Purpose: Advances in high-dose-rate brachytherapy to treat prostate cancer hinge on improved accuracy in navigation and targeting while optimizing a streamlined workflow. Multimodal image registration and electromagnetic (EM) tracking are two technologies integrated into a prototype system in the early phase of clinical evaluation. We aim to report on the system's accuracy and workflow performance in support of tumor-targeted procedures.

Novel O-[C]-methylated derivatives of the neprilysin inhibitor sacubitril: Radiosynthesis, autoradiography and plasma stability evaluation.

Introduction: The O-[C]methylated derivatives of the clinically used neprilysin inhibitor (NEPi) sacubitril ([C]SacOMe, (2R,4S)-ethyl 5-([biphenyl]-4-yl)-4-(4-[C]methoxy-4-oxobutanamido)-2-methylpentanoate) and LBQ657 ([C]MeOLBQ, (2R,4S)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid [C]methyl ester and [C]LBQOMe, (2R,4S)-5-(biphenyl-4-yl)-4-[(4-[C]methoxy-4-oxobutanamido)]-2-methylpentanoic acid) were evaluated to determine their potential as PET imaging tracers and investigate the effect of such labeling esterification on neprilysin (NEP) binding.

Methods: [C]MeOLBQ, [C]SacOMe and [C]LBQOMe were synthesized by O-[C]methylation using [C]methyl triflate. Binding of these radiolabeled derivatives (5 nM) were assessed by autoradiography on rat neprilysin rich kidney slices with or without 10 μM NEPi (thiorphan or sacubitril) for 20 min at 37 °C.

Evaluation of the high affinity [F]fluoropyridine-candesartan in rats for PET imaging of renal AT receptors.

Introduction: Alterations in the expression of the Angiotensin II type 1 receptors (ATR) have been demonstrated in the development of several heart and renal diseases. The aim of this study was to evaluate the novel compound [F]fluoropyridine-candesartan as a PET imaging tracer of ATR in rat kidneys.

Methods: Competition binding assays were carried out with membranes from CHO-K1 cells expressing human ATR.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development.

Results: This commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals.

Conclusion: Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

Development of a novel [ F]fluorobenzyl derivative of the AT receptor antagonist Candesartan.

Candesartan is a clinically approved angiotensin II type 1 receptor (AT R)-blocker that selectively binds AT Rs in high affinity. We report here the radiosynthesis and automation of the novel [ F]fluorobenzyl derivative of Candesartan using the Sonogashira cross-coupling reaction. [ F]Fluorobenzyl-Candesartan ([ F]7) was developed from 4-[ F]fluoroiodobenzene ([ F]FIB) that was conjugated with alkyne-trityl-candesartan with the assistance of a Pd (PPh ) /CuI catalyst followed by acid deprotection.

Synthesis of a C-Isotopologue of the B-Raf-Selective Inhibitor Encorafenib Using In-Loop [C]CO Fixation.

The serine/threonine kinase B-Raf is an essential regulator of cellular growth, differentiation, and survival. B-Raf protein expression is elevated throughout melanoma progression, making it an attractive target for noninvasive imaging using positron-emission tomography. Encorafenib is a potent and highly selective inhibitor of B-Raf used in the clinical management of melanoma.

Synthesis of the Novel AT Receptor Tracer [F]Fluoropyridine-Candesartan via Click Chemistry.

A novel 7-((4-(3-((2-[F]fluoropyridin-3-yl)oxy)propyl)-1-1,2,3-triazol-1-yl)methyl)-1-benzo[]imidazole derivative of the angiotensin II type-1 receptor (ATR) blocker candesartan, [F]fluoropyridine-candesartan, was synthesized via the copper-catalyzed azide-alkyne cycloaddition click reaction between 2-[F]fluoro-3-(pent-4-yn-1-yloxy)pyridine ([F]FPyKYNE) and the tetrazole-protected azido-candesartan derivative, followed by acid deprotection. This three-step, two-pot, and two-step purification synthesis was done within 2 h. The use of tris[(1-hydroxypropyl-1-1,2,3-triazol-4-yl)methyl]amine (THPTA) as a Cu(I) stabilizing agent increased the overall radiochemical yield by 4-fold (10 ± 2%, = 13) compared to the reaction without THPTA (2.

Radiosynthesis of the C-methyl derivative of LBQ657 for PET investigation of the neprilysin inhibitor sacubitril.

Neprilysin, also known as neutral endopeptidase, is a cell surface membrane metalo-endopeptidase that cleaves various peptides. Altered neprilysin expression has been correlated with various cancers and cardiovascular diseases. In this work, we present the radiosynthesis of the novel O- C-methylated derivative of LBQ657 (a potent neprilysin inhibitor).

Reliable quantification of myocardial sympathetic innervation and regional denervation using [C]meta-hydroxyephedrine PET.

Purpose: Cardiac sympathetic nervous system (SNS) dysfunction is associated with poor prognosis in chronic heart failure patients. This study characterized the reproducibility and repeatability of [C]meta-hydroxyephedrine (HED) positron emission tomography (PET) quantification of cardiac SNS innervation, regional denervation, and myocardial blood flow (MBF).

Methods: Dynamic HED PET-CT scans were performed 47 ± 22 days apart in 20 patients with stable heart failure and reduced ejection fraction.

SPECT and PET imaging of adrenomedullin receptors: a promising strategy for studying pulmonary vascular diseases.

Circulating adrenomedullin (AM) levels are elevated in several cardiovascular diseases, including pulmonary vascular diseases causing pulmonary hypertension. To date the perfusion agent Tc-albumin macroaggregates (MAA) is the only approved radiopharmaceutical used for imaging of pulmonary circulation. Unlike Tc-MAA, imaging the AM receptors involves a molecular process dependent on the density of the receptors and the affinity of specific radioligands.

Al[F]F-complexation of DFH17, a NOTA-conjugated adrenomedullin analog, for PET imaging of pulmonary circulation.

Introduction: Adrenomedullin receptors are highly expressed in human alveolar capillaries and provide a molecular target for imaging the integrity of pulmonary microcirculation. In this work, we aimed to develop a NOTA-derivatized adrenomedullin analog (DFH17), radiolabeled with [F]AlF, for PET imaging of pulmonary microcirculation.

Methods: Highly concentrated [F](AlF) (15 μL) was produced from purified fluorine-18 in NaCl 0.

Simplified and robust one-step radiosynthesis of [ F]DCFPyL via direct radiofluorination and cartridge-based purification.

[ F]DCFPyL is a clinical-stage PET radiotracer used to image prostate cancer. This report details the efficient production of [ F]DCFPyL using single-step direct radiofluorination, without the use of carboxylic acid-protecting groups. Radiolabeling reaction optimization studies revealed an inverse correlation between the amount of precursor used and the radiochemical yield.

Treatment with enalapril and not diltiazem ameliorated progression of chronic kidney disease in rats, and normalized renal AT1 receptor expression as measured with PET imaging.

ACE inhibitors are considered first line of treatment in patients with many forms of chronic kidney disease (CKD). Other antihypertensives such as calcium channel blockers achieve similar therapeutic effectiveness in attenuating hypertension-related renal damage progression. Our objective was to explore the value of positron emission tomography (PET) imaging of renal AT1 receptor (AT1R) to guide therapy in the 5/6 subtotal-nephrectomy (Nx) rat model of CKD.

Effects of an endothelin receptor antagonist, Macitentan, on right ventricular substrate utilization and function in a Sugen 5416/hypoxia rat model of severe pulmonary arterial hypertension.

Background: Altered myocardial energy metabolism has been linked to worsening of RV function in pulmonary arterial hypertension (PAH). The aim of this study was to evaluate RV glucose and fatty acid metabolism in vivo in a rat model of PAH using positron emission tomography (PET) and investigate the effects of Macitentan on RV substrate utilization.

Methods: PAH was induced in male Sprague-Dawley rats by a single subcutaneous injection of Sugen 5416 (20 mg/kg) followed by 3 weeks of hypoxia (10% oxygen).

Long-Term Follow-Up of Outcomes With F-18-Fluorodeoxyglucose Positron Emission Tomography Imaging-Assisted Management of Patients With Severe Left Ventricular Dysfunction Secondary to Coronary Disease.

Background: Whether viability imaging can impact long-term patient outcomes is uncertain. The PARR-2 study (Positron Emission Tomography and Recovery Following Revascularization) showed a nonsignificant trend toward improved outcomes at 1 year using an F-18-fluorodeoxyglucose positron emission tomography (PET)-assisted strategy in patients with suspected ischemic cardiomyopathy. When patients adhered to F-18-fluorodeoxyglucose PET recommendations, outcome benefit was observed.

Decreased renal AT1 receptor binding in rats after subtotal nephrectomy: PET study with [(18)F]FPyKYNE-losartan.

Background: Significant renal mass reduction induced by 5/6 subtotal nephrectomy (Nx) is associated with a chain of events that culminates in hypertension and chronic kidney disease (CKD). Numerous studies have provided evidence for the role of angiotensin (Ang) II type 1 receptor (AT1R) in the promotion and progression of the disease; however, conflicting results were reported on intrarenal AT1R levels in CKD models.

Methods: Male Sprague-Dawley rats (n = 26) underwent Nx or sham operations.

Characterization of 18F-FPyKYNE-Losartan for Imaging AT1 Receptors.

Unlabelled: Most physiologic effects of the renin angiotensin system (RAS) are mediated via the angiotensin (Ang) type 1 receptor (ATR). The F-FPyKYNE derivative of the clinically used ATR blocker losartan exhibits high binding selectivity for kidney ATR and rapid metabolism in rats. The aim of this study was to further assess the binding profile of this novel PET agent for imaging ATR in rats and pigs.

Deletion of MLIP (muscle-enriched A-type lamin-interacting protein) leads to cardiac hyperactivation of Akt/mammalian target of rapamycin (mTOR) and impaired cardiac adaptation.

Aging and diseases generally result from tissue inability to maintain homeostasis through adaptation. The adult heart is particularly vulnerable to disequilibrium in homeostasis because its regenerative abilities are limited. Here, we report that MLIP (muscle enriched A-type lamin-interacting protein), a unique protein of unknown function, is required for proper cardiac adaptation.

Evaluation of [(11)C]methyl-losartan and [(11)C]methyl-EXP3174 for PET imaging of renal AT1receptor in rats.

Introduction: The angiotensin II type 1 receptor (AT1R) is responsible for the main effects of the renin-angiotensin system (RAS), and its expression pattern is altered in several diseases. The [(11)C]methylated derivatives of the clinically used AT1R blocker (ARB) losartan and its active metabolite EXP3174, that binds with higher affinity to AT1R, were evaluated as potential PET imaging tracers in rat kidneys.

Methods: [(11)C]Methyl-losartan and [(11)C]methyl-EXP3174 were synthesized by [(11)C]methylation of the tetrazole-protected analogs using [11C]methyl iodide.

Test-retest repeatability of myocardial blood flow and infarct size using ¹¹C-acetate micro-PET imaging in mice.

Purpose: Global and regional responses of absolute myocardial blood flow index (iMBF) are used as surrogate markers to assess response to therapies in coronary artery disease. In this study, we assessed the test-retest repeatability of iMBF imaging, and the accuracy of infarct sizing in mice using (11)C-acetate PET.

Methods: (11)C-Acetate cardiac PET images were acquired in healthy controls, endothelial nitric oxide synthase (eNOS) knockout transgenic mice, and mice after myocardial infarction (MI) to estimate global and regional iMBF, and myocardial infarct size compared to (18)F-FDG PET and ex-vivo histology results.

Shifts in myocardial fatty acid and glucose metabolism in pulmonary arterial hypertension: a potential mechanism for a maladaptive right ventricular response.

Aims: We investigated the role of metabolic alterations in the development of a maladaptive right ventricular (RV) response in pulmonary arterial hypertension (PAH), which has not previously been undertaken. This study evaluated relationships between glucose and fatty acid metabolism obtained using PET with invasive pulmonary haemodynamics, RV measurements, and RV function to gain insight into the mechanism of RV maladaptation.

Methods And Results: Seventeen consecutive PAH patients (mean age 56 ± 15) who underwent right heart catheterization [mean pulmonary arterial pressure (mPAP) 43 ± 12 mmHg] had cardiac 18F-fluoro-2-deoxyglucose (FDG) and (18)F-fluoro-6-thioheptadecanoic acid (FTHA) PET imaging.