Short-Term Biological Toxicity Prediction of [177Lu]Lutetium-Oxodotreotide: An Original Retrospective Analysis.

Introduction: [177Lu]Lutetium (Lu)-oxodotreotide is a radiopharmaceutical drug used as peptide receptor radionuclide therapy (PRRT) for somatostatin receptor-expressing neuroendocrine neoplasms. It provides an additional effective alternative treatment for these rare cancers. Although well tolerated, its safety profile must continue to be characterized to support its use as a first-line treatment or for additional cycles. This study evaluated factors associated with the occurrence of [177Lu]Lu-oxodotreotide induced short-term toxicity. Materials and Methods: A retrospective observational monocentric study was carried out from July 2013 to October 2021. Inclusion criteria were defined as follows: patients who received at least four cycles of [177Lu]Lu-oxodotreotide and were followed up for 6 months after the last injection. Graduated toxicity was defined using the National Cancer Institute Common Terminology Criteria for Adverse Events 5.0. Cox regression was used in the analysis. Results: Forty patients were included. The most frequent toxicities occurred during the first cycle and were graded as G1 or G2. As expected, toxicities were predominantly hematological and hepatic, with incomplete reversibility after each cycle. The following factors were significantly related to the occurrence of hematological or hepatic toxicity during PRRT: gastrointestinal primary tumor diagnosis, bone metastases, peritoneal metastases, pancreatic metastases or pulmonary metastases, and high tumor grade. Conclusion: Knowledge and consideration of these factors in adjusting [177Lu]Lu-oxodotreotide treatment regimen could help prevent or reduce the severity of these toxicities. Further studies are still warranted to refine these results and improve treatment management.

Design and preclinical evaluation of a novel apelin-based PET radiotracer targeting APJ receptor for molecular imaging of angiogenesis.

APJ has been extensively described in the pathophysiology of angiogenesis and cell proliferation. The prognostic value of APJ overexpression in many diseases is now established. This study aimed to design a PET radiotracer that specifically binds to APJ. Apelin-F13A-NODAGA (AP747) was synthesized and radiolabeled with gallium-68 ([68Ga]Ga-AP747). Radiolabeling purity was excellent (> 95%) and stable up to 2 h. Affinity constant of [67Ga]Ga-AP747 was measured on APJ-overexpressing colon adenocarcinoma cells and was in nanomolar range. Specificity of [68Ga]Ga-AP747 for APJ was evaluated in vitro by autoradiography and in vivo by small animal PET/CT in both colon adenocarcinoma mouse model and Matrigel plug mouse model. Dynamic of [68Ga]Ga-AP747 PET/CT biodistributions was realized on healthy mice and pigs for two hours, and quantification of signal in organs showed a suitable pharmacokinetic profile for PET imaging, largely excreted by urinary route. Matrigel mice and hindlimb ischemic mice were submitted to a 21-day longitudinal follow-up with [68Ga]Ga-AP747 and [68Ga]Ga-RGD2 small animal PET/CT. [68Ga]Ga-AP747 PET signal in Matrigel was significantly more intense than that of [68Ga]Ga-RGD2. Revascularization of the ischemic hind limb was followed by LASER Doppler. In the hindlimb, [68Ga]Ga-AP747 PET signal was more than twice higher than that of [68Ga]Ga-RGD2 on day 7, and significantly superior over the 21-day follow-up. A significant, positive correlation was found between the [68Ga]Ga-AP747 PET signal on day 7 and late hindlimb perfusion on day 21. We developed a new PET radiotracer that specifically binds to APJ, [68Ga]Ga-AP747 that showed more efficient imaging properties than the most clinically advanced tracer of angiogenesis, [68Ga]Ga-RGD2.

Sublingual Atropine Administration as a Tool to Decrease Salivary Glands' PSMA-Ligand Uptake: A Preclinical Proof of Concept Study Using [68Ga]Ga-PSMA-11.

Prostate Specific Membrane Antigen (PSMA)-directed radionuclide therapy has gained an important role in the management of advanced castration-resistant prostate cancer. Although extremely promising, the prolongation in survival and amelioration of disease-related symptoms must be balanced against the direct toxicities of the treatment. Xerostomia is amongst the most common and debilitating of these, particularly when using an alpha emitter. It is therefore of main importance to develop new preventive strategies. This preclinical study has evaluated the effect of α-adrenergic and anticholinergic drugs on [99mTc]TcO4− Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) and [68Ga]Ga-PSMA-11 Positron Emission Tomography (PET/CT). Methods: The effects of phenylephrine, scopolamine, atropine, and ipratropium on salivary glands uptake were evaluated in non-tumor-bearing mice by [99mTc]TcO4− microSPECT/CT. The most efficient identified strategy was evaluated in non-tumor-bearing and xenografted mice by [68Ga]Ga-PSMA-11 PET/CT. Results: Scopolamine and atropine showed a significant decrease in the parotid glands' uptake on SPECT/CT whereas phenylephrine and ipratropium failed. Atropine premedication (sublingual route), which was the most effective strategy, also showed a drastic decrease of [68Ga]Ga-PSMA-11 salivary glands' uptake in both non-tumor-bearing mice (−51.6% for the parotids, p < 0.0001) and human prostate adenocarcinoma xenografted mice (−26.8% for the parotids, p < 0.0001). Conclusion: Premedication with a local administration of atropine could represent a simple, safe, and efficient approach for reducing salivary glands' uptake.

Tracking Radiolabeled Endothelial Microvesicles Predicts Their Therapeutic Efficacy: A Proof-of-Concept Study in Peripheral Ischemia Mouse Model Using SPECT/CT Imaging.

Microvesicles, so-called endothelial large extracellular vesicles (LEVs), are of great interest as biological markers and cell-free biotherapies in cardiovascular and oncologic diseases. However, their therapeutic perspectives remain limited due to the lack of reliable data regarding their systemic biodistribution after intravenous administration. METHODS: Applied to a mouse model of peripheral ischemia, radiolabeled endothelial LEVs were tracked and their in vivo whole-body distribution was quantified by microSPECT/CT imaging. Hindlimb perfusion was followed by LASER Doppler and motility impairment function was evaluated up to day 28 post-ischemia. RESULTS: Early and specific homing of LEVs to ischemic hind limbs was quantified on the day of ischemia and positively correlated with reperfusion intensity at a later stage on day 28 after ischemia, associated with an improved motility function. CONCLUSIONS: This concept is a major asset for investigating the biodistribution of LEVs issued from other cell types, including cancer, thus partly contributing to better knowledge and understanding of their fate after injection.

Comparison of a New 68Ga-Radiolabelled PET Imaging Agent sCD146 and RGD Peptide for In Vivo Evaluation of Angiogenesis in Mouse Model of Myocardial Infarction.

Ischemic vascular diseases are associated with elevated tissue expression of angiomotin (AMOT), a promising molecular target for PET imaging. On that basis, we developed an AMOT-targeting radiotracer, 68Ga-sCD146 and performed the first in vivo evaluation on a myocardial infarction mice model and then, compared AMOT expression and αvß3-integrin expression with 68Ga-sCD146 and 68Ga-RGD2 imaging. After myocardial infarction (MI) induced by permanent ligation of the left anterior descending coronary artery, myocardial perfusion was evaluated by Doppler ultrasound and by 18F-FDG PET imaging. 68Ga-sCD146 and 68Ga-RGD2 PET imaging were performed. In myocardial infarction model, heart-to-muscle ratio of 68Ga-sCD146 imaging showed a significantly higher radiotracer uptake in the infarcted area of MI animals than in sham (* p = 0.04). Interestingly, we also observed significant correlations between 68Ga-sCD146 imaging and delayed residual perfusion assessed by 18F-FDG (* p = 0.04), with lowest tissue fibrosis assessed by histological staining (* p = 0.04) and with functional recovery assessed by ultrasound imaging (** p = 0.01). 68Ga-sCD146 demonstrated an increase in AMOT expression after MI. Altogether, significant correlations of early post-ischemic 68Ga-sCD146 uptake with late heart perfusion, lower tissue fibrosis and better functional recovery, make 68Ga-sCD146 a promising radiotracer for tissue angiogenesis assessment after MI.

Long-term administration of resveratrol at low doses improves neurocognitive performance as well as cerebral blood flow and modulates the inflammatory pathways in the brain.

There is an increasing prevalence of coincident cerebrovascular deficiency and cognitive dysfunction with aging. Increased oxidative stress as well as inflammation that occurs with aging are associated with the impairment of cerebral vascularization. Interestingly, Resveratrol (RSV), a natural phytoalexin, is known to be a strong antioxidant and possesses anti-inflammatory properties. Collectively, these observations strongly suggest that RSV could protect against cerebral vascularization defect and then improves the decline cognitive function associated with aging. In order to test this hypothesis, we investigated the effect of a long-term RSV treatment (1.25 mg/day for 5 months) on cognitive performances of animals that we have allowed to age normally. Then, we further analyzed the gene expression profile and the cerebral blood flow in the brain. By means of novel object recognition (NOR) test, we observed that RSV enhanced NOR performances of aged rats. In addition, RSV enhanced cerebral blood flow during NOR task in aged rats. Using microarrays experiments, we also showed that several pathways related to inflammation and oxidative stress (Eicosanoid signaling, MIF-mediated innate immunity, NF-kB signaling, TNFR2 signaling, IL6 signaling, Production of nitric oxide and ROS) were down-regulated in the brain of RSV treatments rats compared to control rats. In conclusion, these results support that a long-term treatment with RSV improves cognitive performance in the elderly male rat model. This effect is associated with an increase in cerebral blood flow and a decrease in the expression of several pro-inflammatory pathways in the brain.

Succinate Injection Rescues Vasculature and Improves Functional Recovery Following Acute Peripheral Ischemia in Rodents: A Multimodal Imaging Study.

Succinate influences angiogenesis and neovascularization via a hormonelike effect on G-protein-coupled receptor 91 (GPR91). This effect has been demonstrated in the pathophysiology of diabetic retinopathy and rheumatoid arthritis. To evaluate whether succinate can play a role in acute peripheral ischemia, a preclinical study was conducted with ischemic mice treated with succinate or PBS and evaluated by imaging. Acute ischemia was followed by an increased in GPR91 expression in the ischemic muscle. As assessed with LASER-Doppler, succinate treatment resulted in an earlier and more intense reperfusion of the ischemic hindlimb compared to the control group (* p = 0.0189). A microPET study using a radiolabeled integrin ligand ([68Ga]Ga-RGD2) showed an earlier angiogenic activation in the succinate arm compared to control mice (* p = 0.020) with a prolonged effect. Additionally, clinical recovery following ischemia was better in the succinate group. In conclusion, succinate injection promotes earlier angiogenesis after ischemia, resulting in a more effective revascularization and subsequently a better functional recovery.

Pharmaceutical interviews to overcome digestive artefacts on [99m Tc]Tc-tetrofosmin myocardial perfusion scintigraphy.

WHAT IS KNOWN AND OBJECTIVES: Poor image quality was randomly seen in [99m Tc]Tc-tetrofosmin myocardial perfusion scintigraphic imaging. The interference hampered or even precluded medical interpretation. Our objective was to identify the cause of the random interferences. METHODS: Out of 40 patients planned for [99m Tc]Tc-tetrofosmin MPS, 36 presented normal tracer uptake and 4 exhibited subdiaphragmatic artefacts. Pharmaceutical interviews (P.I.) were set up to formally identify aetiologies of subdiaphragmatic uptake of [99m Tc]Tc-tetrofosmin. Patients were questioned about their diet and current drug treatments. RESULTS AND DISCUSSION: P.I. led to identification of dipyridamole as the cause of the artefacts. The systematic ingestion of a solid 25-gram high-fat snack bar and a glass of fresh water was introduced immediately after the injection of dipyridamole in 12 other patients undergoing [99m Tc]Tc-tetrofosmin MPS. None of the 12 patients presented subdiaphragmatic artefacts. WHAT IS NEW AND CONCLUSION: P.I. identified the cause of poor scintigraphic images to allow improved diagnoses.

Renal SPECT/CT with 99mTc-dimercaptosuccinic acid is a non-invasive predictive marker for the development of interstitial fibrosis in a rat model of renal insufficiency.

BACKGROUND: Chronic kidney disease (CKD) increases cardiovascular risk and mortality. Renal fibrosis plays a major role in the progression of CKD but, to date, histology remains the gold standard to assess fibrosis. Non-invasive techniques are needed to assess renal parenchymal impairment and to perform the longitudinal evaluation of renal structure. Thus we evaluated renal isotopic imaging by single-photon emission computed tomography/computed tomography (SPECT/CT) with technetium-99m (99mTc)-dimercaptosuccinic acid (DMSA) to monitor renal impairment during renal insufficiency in rats. METHODS: Renal insufficiency was induced by an adenine-rich diet (ARD) at 0.25 and 0.5% for 28 days. Renal dysfunction was evaluated by assaying biochemical markers and renal histology. Renal parenchymal impairment was assessed by SPECT/CT isotopic imaging with 99mTc-DMSA on Days 0, 7, 14, 21, 28, 35 and 49. RESULTS: Compared with controls, ARD rats developed renal dysfunction characterized by increased serum creatinine and blood urea nitrogen, fibrosis and tubulointerstitial damage in the kidneys, with a dose-dependent effect of the adenine concentration. 99mTc-DMSA SPECT-CT imaging showed a significant decrease in renal uptake over time in 0.25 and 0.5% ARD rats compared with control rats (P = 0.011 and P = 0.0004, respectively). 99mTc-DMSA uptake on Day 28 was significantly inversely correlated with Sirius red staining evaluated on Day 49 (r = 0.89, P < 0.0001, R2 = 0.67). CONCLUSIONS: 99mTc-DMSA renal scintigraphy allows a longitudinal follow-up of risk of renal fibrosis in rats. We found that the reduction of renal parenchyma in ARD rats is inversely proportional to newly formed fibrous tissue in the kidney. Our results suggest that 99mTc-DMSA renal scintigraphy may be a useful non-invasive prognostic marker of the development of renal fibrosis in animals and should be tested in humans.

Silicon-Containing Neurotensin Analogues as Radiopharmaceuticals for NTS1-Positive Tumors Imaging.

Several independent studies have demonstrated the overexpression of NTS1 in various malignancies, which make this receptor of interest for imaging and therapy. To date, radiolabeled neurotensin analogues suffer from low plasmatic stability and thus insufficient availability for high uptake in tumors. We report the development of 68Ga-radiolabeled neurotensin analogues with improved radiopharmaceutical properties through the introduction of the silicon-containing amino acid trimethylsilylalanine (TMSAla). Among the series of novel radiolabeled neurotensin analogues, [68Ga]Ga-JMV6659 exhibits high hydrophilicity (log D7.4 = -3.41 ± 0.14), affinity in the low nanomolar range toward NTS1 (Kd = 6.29 ± 1.37 nM), good selectivity (Kd NTS1/Kd NTS2 = 35.9), and high NTS1-mediated internalization. It has lower efflux and prolonged plasmatic half-life in human plasma as compared to the reference compound ([68Ga]Ga-JMV6661 bearing the minimum active fragment of neurotensin and the same linker and chelate as other analogues). In nude mice bearing HT-29 xenograft, [68Ga]Ga-JMV6659 uptake reached 7.8 ± 0.54 %ID/g 2 h post injection. Uptake was decreased to 1.38 ± 0.71 %ID/g with injection of excess of non-radioactive neurotensin. Radiation dose as extrapolated to human was estimated as 2.35 ± 0.6 mSv for a standard injected activity of 100MBq. [68Ga]Ga-JMV6659 was identified as a promising lead compound suitable for PET imaging of NTS1-expressing tumors.

Surface Charge of Supramolecular Nanosystems for In Vivo Biodistribution: A MicroSPECT/CT Imaging Study.

Bioimaging has revolutionized medicine by providing accurate information for disease diagnosis and treatment. Nanotechnology-based bioimaging is expected to further improve imaging sensitivity and specificity. In this context, supramolecular nanosystems based on self-assembly of amphiphilic dendrimers for single photon emission computed tomography (SPECT) bioimaging are developed. These dendrimers bear multiple In3+ radionuclides at their terminals as SPECT reporters. By replacing the macrocyclic 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid cage with the smaller 1,4,7-triazacyclononane-1,4,7-triacetic acid scaffold as the In3+ chelator, the corresponding dendrimer exhibits neutral In3+ -complex terminals in place of negatively charged In3+ -complex terminals. This negative-to-neutral surface charge alteration completely reverses the zeta-potential of the nanosystems from negative to positive. As a consequence, the resulting SPECT nanoprobe generates a highly sought-after biodistribution profile accompanied by a drastically reduced uptake in liver, leading to significantly improved tumor imaging. This finding contrasts with current literature reporting that positively charged nanoparticles have preferential accumulation in the liver. As such, this study provides new perspectives for improving the biodistribution of positively charged nanosystems for biomedical applications.

Uremic Toxic Blood-Brain Barrier Disruption Mediated by AhR Activation Leads to Cognitive Impairment during Experimental Renal Dysfunction.

BACKGROUND: Uremic toxicity may play a role in the elevated risk of developing cognitive impairment found among patients with CKD. Some uremic toxins, like indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AhR), which is widely expressed in the central nervous system and which we previously identified as the receptor of indoxyl sulfate in endothelial cells. METHODS: To characterize involvement of uremic toxins in cerebral and neurobehavioral abnormalities in three rat models of CKD, we induced CKD in rats by an adenine-rich diet or by 5/6 nephrectomy; we also used AhR-/- knockout mice overloaded with indoxyl sulfate in drinking water. We assessed neurologic deficits by neurobehavioral tests and blood-brain barrier disruption by SPECT/CT imaging after injection of 99mTc-DTPA, an imaging marker of blood-brain barrier permeability. RESULTS: In CKD rats, we found cognitive impairment in the novel object recognition test, the object location task, and social memory tests and an increase of blood-brain barrier permeability associated with renal dysfunction. We found a significant correlation between 99mTc-DTPA content in brain and both the discrimination index in the novel object recognition test and indoxyl sulfate concentrations in serum. When we added indoxyl sulfate to the drinking water of rats fed an adenine-rich diet, we found an increase in indoxyl sulfate concentrations in serum associated with a stronger impairment in cognition and a higher permeability of the blood-brain barrier. In addition, non-CKD AhR-/- knockout mice were protected against indoxyl sulfate-induced blood-brain barrier disruption and cognitive impairment. CONCLUSIONS: AhR activation by indoxyl sulfate, a uremic toxin, leads to blood-brain barrier disruption associated with cognitive impairment in animal models of CKD.

Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease.

Cardiovascular complications observed in chronic kidney disease (CKD) are associated with aryl hydrocarbon receptor (AhR) activation by tryptophan-derived uremic toxins-mainly indoxyl sulfate (IS). AhR is a ligand-activated transcription factor originally characterized as a receptor of xenobiotics involved in detoxification. The aim of this study was to determine the role of AhR in a CKD mouse model based on an adenine diet. Wild-type (WT) and AhR-/- mice were fed by alternating an adenine-enriched diet and a regular diet for 6 weeks. Our results showed an increased mortality rate of AhR-/- males. AhR-/- females survived and developed a less severe renal insufficiency that WT mice, reflected by urea, creatinine, and IS measurement in serum. The protective effect was related to a decrease of pro-inflammatory and pro-fibrotic gene expression, an attenuation of tubular injury, and a decrease of 2,8-dihydroxyadenine crystal deposition in the kidneys of AhR-/- mice. These mice expressed low levels of xanthine dehydrogenase, which oxidizes adenine into 2,8-dihydroxyadenine, and low levels of the IS metabolism enzymes. In conclusion, the CKD model of adenine diet is not suitable for AhR knockout mice when studying the role of this transcription factor in cardiovascular complications, as observed in human CKD.

Design, synthesis, and biological evaluation of a multifunctional neuropeptide-Y conjugate for selective nuclear delivery of radiolanthanides.

BACKGROUND: Targeting G protein-coupled receptors on the surface of cancer cells with peptide ligands is a promising concept for the selective tumor delivery of therapeutically active cargos, including radiometals for targeted radionuclide therapy (TRT). Recently, the radiolanthanide terbium-161 (161Tb) gained significant interest for TRT application, since it decays with medium-energy ß-radiation but also emits a significant amount of conversion and Auger electrons with short tissue penetration range. The therapeutic efficiency of radiometals emitting Auger electrons, like 161Tb, can therefore be highly boosted by an additional subcellular delivery into the nucleus, in order to facilitate maximum dose deposition to the DNA. In this study, we describe the design of a multifunctional, radiolabeled neuropeptide-Y (NPY) conjugate, to address radiolanthanides to the nucleus of cells naturally overexpressing the human Y1 receptor (hY1R). By using solid-phase peptide synthesis, the hY1R-preferring [F7,P34]-NPY was modified with a fatty acid, a cathepsin B-cleavable linker, followed by a nuclear localization sequence (NLS), and a DOTA chelator (compound pb12). In this proof-of-concept study, labeling was performed with either native terbium-159 (natTb), as surrogate for 161Tb, or with indium-111 (111In). RESULTS: [natTb]Tb-pb12 showed a preserved high binding affinity to endogenous hY1R on MCF-7 cells and was able to induce receptor activation and internalization similar to the hY1R-preferring [F7,P34]-NPY. Specific internalization of the 111In-labeled conjugate into MCF-7 cells was observed, and importantly, time-dependent nuclear uptake of 111In was demonstrated. Study of metabolic stability showed that the peptide is insufficiently stable in human plasma. This was confirmed by injection of [111In]In-pb12 in nude mice bearing MCF-7 xenograft which showed specific uptake only at very early time point. CONCLUSION: The multifunctional NPY conjugate with a releasable DOTA-NLS unit represents a promising concept for enhanced TRT with Auger electron-emitting radiolanthanides. Our research is now focusing on improving the reported concept with respect to the poor plasmatic stability of this promising radiopeptide.

A self-assembling amphiphilic dendrimer nanotracer for SPECT imaging.

Bioimaging has revolutionized modern medicine, and nanotechnology can offer further specific and sensitive imaging. We report here an amphiphilic dendrimer able to self-assemble into supramolecular nanomicelles for effective tumor detection using SPECT radioimaging. This highlights the promising potential of supramolecular dendrimer platforms for biomedical imaging.

Have you looked for "stranger things" in your automated PET dose dispensing system? A process and operators qualification scheme.

BACKGROUND: Many nuclear medicine departments have equipped themselves with automated dispensing systems (ADS) for PET radiopharmaceuticals, in both the operators' and the patients' interests. Whether partially or fully automated, to date there is no marketed ADS representing a true "closed-system". Despite the sterile, injectable nature of ready-to-use radiopharmaceutical drug solutions manipulated by these systems, neither manufacturer's recommendation nor literature report was found about specific qualification of the process' sterility, or about operators' qualification on these dispensing systems. We set up a master plan validation in a radiopharmacy equipped with Trasis Unidose®, including: 1) monthly process-simulating media-fill tests and microbiological contamination assessments of the ADS surfaces; 2) initial and periodic qualification of the operators. The microbiological qualification consisted in surface biocontamination assessment on critical zones with Tryptic-Soy agar. The operator qualification consisted in the evaluation of the operators' knowledge and skills for using the ADS. RESULTS: This study highlighted a minor, handborne microbiological contamination on our first assessment, that corrective actions solved. We therefore decided to brief our operators once a month on microbiological control results, hygiene and good practices, with the support of the present case illustrating the biodecontamination efficiency. CONCLUSIONS: As the automation of PET monodose conditioning process still implies human intervention for material preparation and manual biodecontamination, this study illustrates that initial and periodic qualification of the environment and the conditioning process of ADS, including microbiological qualification and operators' qualification, are needed to meet specifications.

A Comprehensive Review of Non-Covalent Radiofluorination Approaches Using Aluminum [18F]fluoride: Will [18F]AlF Replace 68Ga for Metal Chelate Labeling?

Due to its ideal physical properties, fluorine-18 turns out to be a key radionuclide for positron emission tomography (PET) imaging, for both preclinical and clinical applications. However, usual biomolecules radiofluorination procedures require the formation of covalent bonds with fluorinated prosthetic groups. This drawback makes radiofluorination impractical for routine radiolabeling, gallium-68 appearing to be much more convenient for the labeling of chelator-bearing PET probes. In response to this limitation, a recent expansion of the 18F chemical toolbox gave aluminum [18F]fluoride chemistry a real prominence since the late 2000s. This approach is based on the formation of an [18F][AlF]2+ cation, complexed with a 9-membered cyclic chelator such as NOTA, NODA or their analogs. Allowing a one-step radiofluorination in an aqueous medium, this technique combines fluorine-18 and non-covalent radiolabeling with the advantage of being very easy to implement. Since its first reports, [18F]AlF radiolabeling approach has been applied to a wide variety of potential PET imaging vectors, whether of peptidic, proteic, or small molecule structure. Most of these [18F]AlF-labeled tracers showed promising preclinical results and have reached the clinical evaluation stage for some of them. The aim of this report is to provide a comprehensive overview of [18F]AlF labeling applications through a description of the various [18F]AlF-labeled conjugates, from their radiosynthesis to their evaluation as PET imaging agents.

Thromboxane-prostaglandin receptor antagonist, terutroban, prevents neurovascular events after subarachnoid haemorrhage: a nanoSPECT study in rats.

BACKGROUND: Several lipid metabolites in cerebrospinal fluid are correlated with poor outcomes in aneurysmal subarachnoid haemorrhage. Most of these metabolites bind to ubiquitous thromboxane-prostaglandin (TP) receptors, causing vasoconstriction and inflammation. Here, we evaluated terutroban (TBN), a specific TP receptor antagonist, for the prevention of post-haemorrhage blood-brain barrier disruption, neuronal apoptosis and delayed cerebral hypoperfusion. METHODS: The rat double subarachnoid haemorrhage model was produced by twice injecting (days 1 and 2) autologous blood into the cisterna magna. Seventy-eight male Sprague-Dawley rats were assigned to experimental groups. Rats exposed to subarachnoid haemorrhage were allocated to no treatment (SAH group) or TBN treatment by gastric gavage during the first 5 days after haemorrhage (SAH+TBN group). Control rats received artificial cerebrospinal fluid injections (CSF group). Sham-operated rats with or without TBN administration were also studied. Body weight and Garcia neurological scores were assessed on day 2 and day 5. We used nanoscale single-photon emission computed tomography (nanoSPECT) to measure brain uptake of three radiolabelled agents: 99mTechnetium-diethylenetriaminepentacetate (99mTc-DTPA), which indicated blood-brain barrier permeability on day 3, 99mTechnetium-annexin V-128 (99mTc-Anx-V128), which indicated apoptosis on day 4, and 99mTechnetium-hexamethylpropyleneamineoxime (99mTc-HMPAO), which indicated cerebral perfusion on day 5. Basilar artery narrowing was verified histologically, and cerebral TP receptor agonists were quantified. RESULTS: 99mTc-DTPA uptake unveiled blood-brain barrier disruption in the SAH group. TBN mitigated this disruption in the brainstem area. 99mTc-Anx-V128 uptake was increased in the SAH group and TBN diminished this effect in the cerebellum. 99mTc-HMPAO uptake revealed a global decreased perfusion on day 5 in the SAH group that was significantly counteracted by TBN. TBN also mitigated basilar artery vasoconstriction, neurological deficits (on day 2), body weight loss (on day 5) and cerebral production of vasoconstrictors such as Thromboxane B2 and Prostaglandin F2α. CONCLUSIONS: Based on in vivo nanoscale imaging, we demonstrated that TBN protected against blood-brain barrier disruption, exerted an anti-apoptotic effect and improved cerebral perfusion. Thus, TP receptor antagonists showed promising results in treating post-haemorrhage neurovascular events.