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. Three exercise groups performed 1 HIIE session (16 sets of 1 min at 85-90% of peak running speed) at 1 (n = 7), 2 (n = 7), and 3 days (n = 8) following the DOX injection. A sedentary (SED) group of mice (n = 6) did not exercise. Animals underwent echocardiography under light anesthesia (isoflurane 0.5-1%) before and 7 days after the DOX injection. Animals were sacrificed on day 9 and hearts were collected for morphometric and histological analysis. RESULTS: Animals exercising on day 3 had the smallest pre-post reduction in left ventricular fractional shortening (LVFS) (MΔ= -1.7 ± 3.3; p = 0.406) and the SED group had the largest reduction (MΔ=-6.8 ± 7.5; p = 0.009). After reclassification of animals according to their exercise compliance (performing > 8/16 of high-intensity bouts), LVFS in compliant mice was unchanged over time (LVFS MΔ= -1.3 ± 5.6; p = 0.396) while non-compliant animals had a LVFS reduction similar to sedentary animals. There were no significant differences in myocardial histology between groups. CONCLUSIONS: In this pilot murine study, one single HIIE session did not exacerbate acute doxorubicin-induced cardiotoxicity. The timing of the HIIE session following DOX injection and the level of compliance to exercise could influence the negative impact of DOX on cardiac function.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

BACKGROUND: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. MAIN BODY: This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. CONCLUSION: Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field in many aspects.

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. In the present work, we revisited the insights of medicinal chemistry in the current radiopharmaceutical development giving examples in oncology, neurology, and cardiology. In this regard, we overviewed the literature on radiopharmaceutical development to study overexpressed targets such as prostate-specific membrane antigen and fibroblast activation protein in cancer; ß-amyloid plaques and tau protein in brain disorders; and angiotensin II type 1 receptor in cardiac disease. The work addresses concepts in the field of radiopharmacy with a special focus on the potential use of radiopharmaceuticals for nuclear imaging and theranostics.

A Reliable Production System of Large Quantities of [13N]Ammonia for Multiple Human Injections.

[13N]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 [13N]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.d.c) per day. The total manufacturing time, including purification, sterile filtration, reformulation, and quality control (QC) analyses performed before batch release, is approximately 11 min from the End of Bombardment (EOB). The drug product complies with FDA/USP specifications and is supplied in a multidose vial allowing for two doses per patient, two patients per batch (4 doses/batch) on two separate PET scanners simultaneously. After four years of use, this production system has proved to be easy to operate and maintain at low costs. Over the last four years, more than 1000 patients have been imaged using this simplified procedure, demonstrating its reliability for the routine production of large quantities of current Good Manufacturing Practices (cGMP)-compliant [13N]ammonia for human use.

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

Angiotensin II type 1 receptors (AT1 R) blocker losartan is used in patients with renal and cardiovascular diseases. [18 F]fluoropyridine-losartan has shown favorable binding profile for quantitative renal PET imaging of AT1 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 [18 F]fluoropyridine-losartan in very high molar activity. Automated radiosynthesis was performed in a three-step, two-pot, and two-HPLC-purification procedure within 2 h. Pure [18 F]FPyKYNE was obtained by radiofluorination of NO2 PyKYNE and silica-gel-HPLC purification (40 ± 9%), preventing the formation of nitropyridine-losartan in the second step. Conjugation with trityl-losartan azide via click chemistry, followed by acid hydrolysis, C18-HPLC purification and reformulation provided [18 F]fluoropyridine-losartan in 11 ± 2% (decay-corrected from [18 F]fluoride, EOB). Using tris[(1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methyl]-amine (THPTA) as a Cu(I)-stabilizing agent for coupling [18 F]FPyKYNE to the unprotected losartan azide afforded [18 F]fluoropyridine-losartan in similar yields (11 ± 3%, decay-corrected from [18 F]fluoride, EOB). Reverse-phase HPLC was optimized by reducing the pH of the mobile phase to achieve complete purification and high molar activities (467 ± 60 GBq/µmol). The use of radioprotectants prevented tracer radiolysis for 10 h (RCP > 99%). The product passed the quality control testing. This reproducible automated radiosynthesis process will allow in vivo PET imaging of AT1 R expression in several diseases.

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. MATERIALS AND METHODS: In a prospective study, we evaluated the system in 43 consecutive procedures after clinical deployment. We measured workflow efficiency and EM catheter reconstruction accuracy. We also evaluated the system's MRI-TRUS registration accuracy with/without deformation, and with/without y-axis rotation for urethral alignment at initialization. RESULTS: The cohort included 32 focal brachytherapy and 11 integrated boost whole-gland implants. Mean procedure time excluding dose delivery was 38 min (range: 21-83) for focal, and 56 min (range: 38-89) for whole-gland implants; stable over time. EM catheter reconstructions achieved a mean difference between computed and measured free-length of 0.8 mm (SD 0.8, no corrections performed), and mean axial manual corrections 1.3 mm (SD 0.7). EM also enabled the clinical use of a non or partially visible catheter in 21% of procedures. Registration accuracy improved with y-axis rotation for urethral alignment at initialization and with the elastic registration (mTRE 3.42 mm, SD 1.49). CONCLUSION: The system supported tumor-targeting and was implemented with no demonstrable learning curve. EM reconstruction errors were small, correctable, and improved with calibration and control of external distortion sources; increasing confidence in the use of partially visible catheters. Image registration errors remained despite rotational alignment and deformation, and should be carefully considered.

Novel O-[11C]-methylated derivatives of the neprilysin inhibitor sacubitril: Radiosynthesis, autoradiography and plasma stability evaluation.

INTRODUCTION: The O-[11C]methylated derivatives of the clinically used neprilysin inhibitor (NEPi) sacubitril ([11C]SacOMe, (2R,4S)-ethyl 5-([biphenyl]-4-yl)-4-(4-[11C]methoxy-4-oxobutanamido)-2-methylpentanoate) and LBQ657 ([11C]MeOLBQ, (2R,4S)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid [11C]methyl ester and [11C]LBQOMe, (2R,4S)-5-(biphenyl-4-yl)-4-[(4-[11C]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: [11C]MeOLBQ, [11C]SacOMe and [11C]LBQOMe were synthesized by O-[11C]methylation using [11C]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. [11C]LBQOMe was further tested for binding selectivity in the presence of 10 µM of angiotensin-converting enzyme inhibitor (ACEi, captopril) or angiotensin II AT1 receptor blocker (AT1R, losartan). Radioligands were evaluated for their in vitro stability up to 20 min after incubation at 37 °C in rat and human plasma by reverse-phase column-switch HPLC. Non-radioactive SacOMe incubated in rat and human plasma was analyzed by HPLC-coupled with high resolution mass spectrometry (HRMS) to confirm the metabolites' identity. [11C]SacOMe main labeled metabolite was further analyzed by HPLC after incubation in rat kidney slices at 37 °C. RESULTS: The novel [11C]SacOMe and [11C]LBQOMe were produced in 32 ± 3% RCY and 15 ± 6% at EOS (decay-corrected from [11C]CO2, n = 3), high molar activity (407 ± 92 GBq/µmol and 260 ± 92 GBq/µmol), and high chemical (≥90%) and radiochemical (≥99%) purities in a total synthesis time of 31 and 34 min, respectively. High accumulation of [11C]SacOMe and [11C]LBQOMe in kidneys was completely blocked (>99.9%) by pre-incubation with NEPi, whereas [11C]MeOLBQ displayed negligible uptake in autoradiography studies. [11C]LBQOMe binding was not affected by saturating doses of losartan or captopril indicating binding selectivity for NEP. While [11C]SacOMe and [11C]LBQOMe were stable in human plasma (>92%) even after 20 min incubation at 37 °C, rat plasma analyses exhibited >95% biotransformation of [11C]SacOMe, 40% of [11C]LBQOMe and >80% loss of the 11C-methyl group of [11C]MeOLBQ after 5 min of incubation. Comparable results using the non-radioactive SacOMe were obtained by HPLC-HRMS. Radio-HPLC analysis of the extracted activity of rat kidney slices incubated with [11C]SacOMe demonstrated that >95% of the radioactive signal corresponded to [11C]LBQOMe as the main metabolite. CONCLUSION: The desethyl active metabolite of [11C]SacOMe, [11C]LBQOMe, displayed stability in human plasma, binding selectivity for neprilysin over ACE or AT1R in rat kidney slices. Rapid plasmatic dealkylation at the 2-methylbutanoic acid position is in line with the necessity of incorporating the labeling group on oxobutanoic acid side in the strategy to develop a stable O-alkylated labeled derivative of sacubitril.

Evaluation of the high affinity [18F]fluoropyridine-candesartan in rats for PET imaging of renal AT1 receptors.

INTRODUCTION: Alterations in the expression of the Angiotensin II type 1 receptors (AT1R) have been demonstrated in the development of several heart and renal diseases. The aim of this study was to evaluate the novel compound [18F]fluoropyridine-candesartan as a PET imaging tracer of AT1R in rat kidneys. METHODS: Competition binding assays were carried out with membranes from CHO-K1 cells expressing human AT1R. Binding to plasma proteins was assessed by ultrafiltration. Radiolabeled metabolites in rat plasma and kidneys of control and pretreated animals (candesartan 10 mg/kg or losartan 30 mg/kg) were analyzed by column-switch HPLC. Dynamic PET/CT images of [18F]fluoropyridine-candesartan in male Sprague-Dawley rats were acquired for 60 min at baseline, pre-treatment with the AT1R antagonist losartan (30 mg/kg) or the AT2R antagonist PD123,319 (5 mg/kg). RESULTS: Fluoropyridine-candesartan bound with a high affinity for AT1R (Ki = 5.9 ± 1.1 nM), comparable to fluoropyridine-losartan but lower than the parent compound candesartan (Ki = 0.4 ± 0.1 nM). [18F]Fluoropyridine-candesartan bound strongly to plasma proteins (99.3%) and was mainly metabolized to radiolabeled hydrophilic compounds, displaying minimal interference on renal AT1R binding with 82% of unchanged tracer in the kidneys at 20 min post-injection. PET imaging displayed high renal and liver accumulations and slow clearances, with maximum tissue-to-blood ratios of 14 ± 3 and 54 ± 12 in kidney cortex and liver, respectively, at 10 min post-injection. Binding specificity for AT1R was demonstrated with marked reductions in kidney cortex (-84%) and liver (-93%) tissue-to-blood ratios at 20 min post-injection, when blocking with AT1R antagonist losartan (30 mg/kg). No change was observed in kidney cortex of rats pre-treated with AT2R antagonist PD 123,319 (5 mg/kg), confirming binding selectivity for AT1 over AT2 receptors. CONCLUSION: High kidney-to-blood ratios and binding selectivity to renal AT1R combined with tracer in vivo stability displaying minimal interference from labeled metabolites support further PET imaging studies with [18F]fluoropyridine-candesartan.

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.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board (January-June 2020).

BACKGROUND: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to describe trends in the field. RESULTS: This commentary of highlights has resulted in 19 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 [18 F]fluorobenzyl derivative of the AT1 receptor antagonist Candesartan.

Candesartan is a clinically approved angiotensin II type 1 receptor (AT1 R)-blocker that selectively binds AT1 Rs in high affinity. We report here the radiosynthesis and automation of the novel [18 F]fluorobenzyl derivative of Candesartan using the Sonogashira cross-coupling reaction. [18 F]Fluorobenzyl-Candesartan ([18 F]7) was developed from 4-[18 F]fluoroiodobenzene ([18 F]FIB) that was conjugated with alkyne-trityl-candesartan with the assistance of a Pd (PPh3 )4 /CuI catalyst followed by acid deprotection. The three-step two-reactor 2-HPLC purification process was automated resulting in >90% pure [18 F]7 in a RCY of 4.6 ± 1.1% (decay corrected from EOB) and molar activities of 1,406-5,513 GBq/mmol. [18 F]FIB was reproducibly obtained by direct radiofluorination of the mono-iodinated triphenylsulfonium salt in the presence of K222/K2 CO3 in an ~30% yield (decay-corrected). [18 F]7 was stable (>97%) up to 4 h in solution and up to 1 h in rat plasma at 37°C. However, the use of Sonogashira cross-coupling reaction to produce [18 F]7 in high yields and molar activities was found to be challenging for routine use in radiochemistry labs.

Synthesis of a 11C-Isotopologue of the B-Raf-Selective Inhibitor Encorafenib Using In-Loop [11C]CO2 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. In this study, the radiosynthesis of a 11C-isotopologue of encorafenib was developed using an in-loop [11C]CO2 fixation reaction. Optimization of reaction conditions reduced the formation of a radiolabeled side product and improved the isolated yields of [11C]encorafenib (14.5 ± 2.4% radiochemical yield). The process was fully automated using a commercial radiosynthesizer for the production of 6845 ± 888 MBq of [11C]encorafenib in high molar activity (177 ± 5 GBq µmol-1), in high radiochemical purity (99%), and in a formulation suitable for animal injection. An in vitro cellular binding experiment demonstrated saturable binding of the radiotracer to A375 melanoma cells.

Synthesis of the Novel AT1 Receptor Tracer [18F]Fluoropyridine-Candesartan via Click Chemistry.

A novel 7-((4-(3-((2-[18F]fluoropyridin-3-yl)oxy)propyl)-1H-1,2,3-triazol-1-yl)methyl)-1H-benzo[d]imidazole derivative of the angiotensin II type-1 receptor (AT1R) blocker candesartan, [18F]fluoropyridine-candesartan, was synthesized via the copper-catalyzed azide-alkyne cycloaddition click reaction between 2-[18F]fluoro-3-(pent-4-yn-1-yloxy)pyridine ([18F]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-1H-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%, n = 13) compared to the reaction without THPTA (2.4 ± 0.2%, n = 3; decay-corrected from 18F produced at the end-of-beam). Complete separation of [18F]FPyKYNE from its nitro precursor and [18F]fluoropyridine-candesartan from the deprotected azido-candesartan allowed for high molar activities (>380 GBq/µmol) of the tracer. The use of 0.1% trifluoroacetic acid in water for reformulation and the addition of sodium ascorbate to the final formulation (1.6 ± 0.2 GBq/mL, n = 3) prevented tracer radiolysis with >97% radiochemical purity for a period of up to 10 h after the end-of-synthesis. A significant reduction in the uptake (86 ± 3%, n = 8) of the tracer was observed ex vivo in rats (at 20 min postinjection) in the AT1R-rich kidney cortex following pretreatment with saturating doses of the AT1R antagonist candesartan or losartan. This specific binding to AT1R was confirmed in vitro in the rat renal cortex (autoradiography) by a reduction of 26 ± 5% (n = 12) with losartan coincubation (10 µM). These favorable binding properties support further studies to assess the potential of [18F]fluoropyridine-candesartan as a tracer for the positron emission tomography imaging of renal AT1R.

Radiosynthesis of the 11 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-11 C-methylated derivative of LBQ657 (a potent neprilysin inhibitor). (2R,4S)-5-(Biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid [11 C]methyl ester ([11 C]MeOLBQ) is an analog of sacubitril where the alkyl ester is a 11 C-methyl instead of an ethyl. [11 C]MeOLBQ was produced in a one-pot two-step synthesis. The O-11 C-methylation of the pentanoic acid part was done with [11 C]methyl triflate followed by the deprotection of the tert-butyl ester precursor in acidic conditions. [11 C]MeOLBQ ([11 C]7) was produced in 9.5 ± 2.5% RCY (25 ± 6% decay-corrected from [11 C]CO2 , n = 3) high molar activity 348 ± 100 GBq/µmol (9425 ± 2720 mCi/µmol) at EOS, in high chemical (>95%) and radiochemical (>99%) purities. The total synthesis time including HPLC purification and reformulation was 29 minutes. To our knowledge, this is the first PET-labeled analog of the clinically used NEP inhibitor sacubitril.

Reliable quantification of myocardial sympathetic innervation and regional denervation using [11C]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 [11C]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. Three observers, blinded to clinical data, used FlowQuant® to evaluate the test-retest repeatability and inter- and intra-observer reproducibility of HED tracer uptake and clearance rates to measure global (LV-mean) retention index (RI), volume of distribution (VT), and MBF. Values were also compared with and without regional partial-volume correction. Regional denervation was quantified as %LV defect size of values < 75% of the LV-maximum. Test-retest repeatability and observer reproducibility were evaluated using intra-class-correlation (ICC) and Bland-Altman coefficient of repeatability (NPC). RESULTS: Intra- and inter-observer correlations of both VT and RI were excellent (ICC = 0.93-0.99). Observer reproducibility (NPC = 3-13%) was lower than test-retest repeatability (NPC = 12-61%). Both regional (%LV defect size) and global (LV-mean) measures of sympathetic innervation were more repeatable using the simple RI model compared to VT (NPC = 12% vs. 19% and 30% vs. 54%). Using either model, quantification of regional denervation (defect size) was consistently more reliable than the global LV-mean values of RI or VT. Regional partial-volume correction degraded repeatability of both the global and regional VT measures by 2-12%. Test-retest repeatability of MBF estimation was relatively poor (NPC = 30-61%) compared with the RI. CONCLUSIONS: Quantitative measures of global and regional SNS innervation were most repeatable using the simple RI method of analysis compared with the more complex VT. Observer variability was significantly lower than the test-retest repeatability using a highly automated analysis program. These results support the use of the simple RI method for reliable analysis of HED PET images in clinical research studies for future evaluation of new therapies and for risk stratification in patients with heart failure.

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 99mTc-albumin macroaggregates (MAA) is the only approved radiopharmaceutical used for imaging of pulmonary circulation. Unlike 99mTc-MAA, imaging the AM receptors involves a molecular process dependent on the density of the receptors and the affinity of specific radioligands. The AM receptors are abundantly distributed in lung capillaries and its integrity provides protection in the development of pulmonary vascular diseases. This review summarizes the development and characterization of radioligands for in vivo imaging of AM receptors as an early predictor of the onset of a pulmonary vascular disease.

Al[18F]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 [18F]AlF, for PET imaging of pulmonary microcirculation. METHODS: Highly concentrated [18F](AlF)2+ (15 µL) was produced from purified fluorine-18 in NaCl 0.9%. Various complexation experiments were carried out at Al-to-NOTA molar ratios ranging from 1:1 to 1:40 to assess optimal radiolabeling conditions before using the peptide. DFH17 peptide (2 mM, pH 4) was radiolabeled with [18F](AlF)2+ for 15 min at 100 °C in a total volume of 60 µL. As part of the radiolabeling process, parameters such as fluorine-18 activity (~37 and 1480 MBq), concentration of AlCl3 (0.75, 2, 3, 6 or 10 mM) and the effects of hydrophilic organic solvent (aqueous vs ethanol 50%) were studied. The final formulation was tested for purity, identity and stability in saline. Initial in vivo evaluation of [18F]AlF-DFH17 was performed in normal rats by PET/CT. RESULTS: The scaled-up production of [18F]AlF-DFH17 was performed in high radiochemical and chemical purities in an overall radiochemical yield of 22-38% (at end-of-synthesis) within 60 min. The final formulation was stable in saline at different radioactive concentrations for 8 h. PET evaluation in rats revealed high lung-to-background ratios and no defluorination in vivo up to 1 h post-injection. CONCLUSION: The novel radioconjugate [18F]AlF-DFH17 appears to be a promising PET ligand for pulmonary microcirculation imaging.

Simplified and robust one-step radiosynthesis of [18 F]DCFPyL via direct radiofluorination and cartridge-based purification.

[18 F]DCFPyL is a clinical-stage PET radiotracer used to image prostate cancer. This report details the efficient production of [18 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. This simplified approach enabled automated preparation of [18 F]DCFPyL within 28 minutes using HPLC purification (26% ± 6%, at EOS, n = 4), which was then scaled up for large-batch production to generate 1.46 ± 0.23 Ci of [18 F]DCFPyL at EOS (n = 7) in high molar activity (37 933 ± 4158 mCi/µmol, 1403 ± 153 GBq/µmol, at EOS, n = 7). Further, this work enabled the development of [18 F]DCFPyL production in 21 minutes using an easy cartridge-based purification (25% ± 9% radiochemical yield, at EOS, n = 3).

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. Ten weeks after Nx, Sprague-Dawley rats were administered 10mg/kg/d enalapril (NxE), 30mg/kg/d diltiazem (NxD) or left untreated (Nx) for an additional 8-10 weeks. Kidney AT1R expression was assessed using in vivo [18F]fluoropyridine-losartan PET and in vitro autoradiography. Compared to shams, Nx rats exhibited higher systolic blood pressure that was reduced by both enalapril and diltiazem. At 18-20 weeks, plasma creatinine and albuminuria were significantly increased in Nx, reduced to sham levels in NxE, but enhanced in NxD rats. Enalapril treatment decreased kidney angiotensin II whereas diltiazem induced significant elevations in plasma and kidney levels. Reduced PET renal AT1R levels in Nx were normalized by enalapril but not diltiazem, and results were supported by autoradiography. Reduction of renal blood flow in Nx was restored by enalapril, while no difference was observed in myocardial blood flow amongst groups. Enhanced left ventricle mass in Nx was not reversed by enalapril but was augmented with diltiazem. Stroke volume was diminished in untreated Nx compared to shams and restored with both therapies. [18F]Fluoropyridine-Losartan PET allowed in vivo quantification of kidney AT1R changes associated with progression of CKD and with various pharmacotherapies.