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Coccygodynia, or tailbone pain, is the most common in women after trauma (complicated childbirth, fall). This pain can be treated conservatively (by using analgesics, local injections, physiotherapy) or by surgical coccygectomy. In the presented article, a set of five female patients is evaluated, in whom, after the failing conservative therapy, coccygectomy was indicated for persistent coccygodynia. In all female patients, improvement of their clinical condition and alleviation of pain were reported. Coccygectomy has its place in the management of coccygodynia and in correctly chosen patients significant pain reduction can be expected. [ABSTRACT FROM AUTHOR]

PURPOSE OF THE STUDY Sacroiliac joint dysfunction is defined as a permanent chronic pain originating from the sacroiliac joint, limiting the patient’s daily activities. The purpose of this study was to evaluate the effectiveness of the minimally invasive sacroiliac joint stabilization by triangular titanium implants in patients with sacroiliac joint dysfunction. MATERIAL AND METHODS The prospective study evaluated the patients who had underwent a minimally invasive sacroiliac joint stabilization for sacroiliac joint dysfunction with the use of iFuse® implants. The surgery was performed solely under fluoroscopic guidance or together with the use of O-arm O2® mobile imaging system. The clinical condition, the Visual Analogue Scale preoperatively and one year postoperatively, previous surgeries in the lumbar spine region, the use of O-arm and occurrence of complications were recorded. The minimum follow-up period was 1 year. RESULTS The group was composed of 20 patients, of whom 4 men and 16 women. The mean age was 48.9 years. The surgeries covered 21 sacroiliac joints. Improvement of the clinical condition was reported in 17 cases (81.0%), no relief was observed in 4 cases (19%). The mean VAS score was 6.1 points preoperatively and decreased to 2.9 points postoperatively (p=0.0001). CONCLUSIONS The minimally invasive sacroiliac joint stabilization should be reserved for patients experiencing an intractable pain originating from the sacroiliac joint, in whom all non-operative therapy failed. [ABSTRACT FROM AUTHOR]

Purpose: Preclinical imaging, with translational potential, lacks a standardized method for defining volumes of interest (VOIs), impacting data reproducibility. The aim of this study was to determine the interobserver variability of VOI sizes and standard uptake values (SUV mean and SUV max ) of different organs using the same [ 18 F]FDG-PET and PET/CT datasets analyzed by multiple observers. In addition, the effect of a standardized analysis approach was evaluated., Procedures: In total, 12 observers (4 beginners and 8 experts) analyzed identical preclinical [ 18 F]FDG-PET-only and PET/CT datasets according to their local default image analysis protocols for multiple organs. Furthermore, a standardized protocol was defined, including detailed information on the respective VOI size and position for multiple organs, and all observers reanalyzed the PET/CT datasets following this protocol., Results: Without standardization, significant differences in the SUV mean and SUV max were found among the observers. Coregistering CT images with PET images improved the comparability to a limited extent. The introduction of a standardized protocol that details the VOI size and position for multiple organs reduced interobserver variability and enhanced comparability., Conclusions: The protocol offered clear guidelines and was particularly beneficial for beginners, resulting in improved comparability of SUV mean and SUV max values for various organs. The study suggested that incorporating an additional VOI template could further enhance the comparability of the findings in preclinical imaging analyses., (© 2024. The Author(s).)

Since the discovery of cisplatin's antitumoral activity and its approval as an anticancer drug, significant efforts have been made to enhance its physiological stability and anticancer efficacy and to reduce its side effects. With the rapid development of targeted and personalized therapies, and the promising theranostic approach, platinum drugs have found new opportunities in more sophisticated systems. Theranostic agents combine diagnostic and therapeutic moieties in one scaffold, enabling simultaneous disease monitoring, therapy delivery, response tracking, and treatment efficacy evaluation. In these systems, the platinum core serves as the therapeutic agent, while the functionalized ligand provides diagnostic tools using various imaging techniques. This review aims to highlight the significant role of platinum-based complexes in theranostic applications, and, to the best of our knowledge, this is the first focused contribution on this type of platinum compounds. This review presents a brief introduction to the development of platinum chemotherapeutic drugs, their limitations, and resistance mechanisms. It then describes recent advancements in integrating platinum complexes with diagnostic agents for both tumor treatment and monitoring. The main body is organized into three categories based on imaging techniques: fluorescence, positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI). Finally, this review outlines promising strategies and future perspectives in this evolving field.

Cholangiocarcinoma (CCA) is a type of primary liver cancer originating from the biliary tract epithelium, characterized by limited treatment options for advanced cases and low survival rates. This study aimed to establish an orthotopic mouse model for CCA and monitor tumor growth using PET/MR imaging. Murine CCA cells were implanted into the liver lobe of male C57BL/6J mice. The imaging groups included contrast-enhanced (CE) MR, CE-MR with static [ 18 F]FDG-PET, and dynamic [ 18 F]FDG-PET. Tumor volume and FDG uptake were measured weekly over four weeks. Early tumor formation was visible in CE-MR images, with a gradual increase in volume over time. Dynamic FDG-PET revealed an increase in the metabolic glucose rate (MRGlu) over time. Blood analysis showed pathological changes in liver-related parameters. Lung metastases were observed in nearly all animals after four weeks. The study concludes that PET-MR imaging effectively monitors tumor progression in the CCA mouse model, providing insights into CCA development and potential treatment strategies.

Nanodiamonds (NDs) are emerging as a novel nanoparticle class with growing interest in medical applications. The surface coating of NDs can be modified by attaching binding ligands or imaging probes, turning them into multi-modal targeting agents. In this investigation, we assessed the targeting efficacy of octreotide-functionalized 68 Ga-radiolabelled NDs for cancer imaging and compared it with the tumor uptake using [ 68 Ga]Ga-DOTA-TOC. In vivo studies in mice bearing AR42J tumors demonstrated the highest accumulation of the radiolabeled functionalized NDs in the liver and spleen, with relatively low tumor uptake compared to [ 68 Ga]Ga-DOTA-TOC. Our findings suggest that, within the scope of this study, functionalization did not enhance the tumor-targeting capabilities of NDs.

P-glycoprotein (P-gp, encoded in humans by the ABCB1 gene and in rodents by the Abcb1a/b genes) is a membrane transporter that can restrict the intestinal absorption and tissue distribution of many drugs and may also contribute to renal and hepatobiliary drug excretion. The aim of this study was to compare the performance and sensitivity of currently available radiolabeled P-gp substrates for positron emission tomography (PET) with the single-photon emission computed tomography (SPECT) radiotracer [ 99m Tc]Tc-sestamibi for measuring the P-gp function in the kidneys and liver. Wild-type, heterozygous ( Abcb1a/b (+/ - ) ), and homozygous ( Abcb1a/b ( - / - ) ) Abcb1a/b knockout mice were used as models of different P-gp abundance in excretory organs. Animals underwent either dynamic PET scans after intravenous injection of [ 11 C] N -desmethyl-loperamide, ( R )-[ 11 C]verapamil, or [ 11 C]metoclopramide or consecutive static SPECT scans after intravenous injection of [ 99m Tc]Tc-sestamibi. P-gp in the kidneys and liver of the mouse models was analyzed with immunofluorescence labeling and Western blotting. In the kidneys, Abcb1a/b () mice had intermediate P-gp abundance compared with wild-type and Abcb1a/b (-/-) mice. Among the four tested radiotracers, renal clearance of radioactivity (CL urine,kidney ) was significantly reduced (-83%) in Abcb1a/b ( - / - ) mice only for [ 99m Tc]Tc-sestamibi. Biliary clearance of radioactivity (CL bile,liver ) was significantly reduced in Abcb1a/b ( - / - ) mice for [ 11 C] N -desmethyl-loperamide (-47%), [ 11 C]metoclopramide (-25%), and [ 99m Tc]Tc-sestamibi (-79%). However, in Abcb1a/b (+/ - ) mice, CL bile,liver was significantly reduced (-47%) only for [ 99m Tc]Tc-sestamibi. Among the tested radiotracers, [ 99m Tc]Tc-sestamibi performed best in measuring the P-gp function in the kidneys and liver. Owing to its widespread clinical availability, [ 99m Tc]Tc-sestamibi represents a promising probe substrate to assess systemic P-gp-mediated drug-drug interactions and to measure renal and hepatic P-gp function under different (patho-)physiological conditions.

The efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier limits the cerebral uptake of various xenobiotics. To assess the sensitivity of [ 11 C]metoclopramide to measure decreased cerebral P-gp function, we performed [ 11 C]metoclopramide PET scans without (baseline) and with partial P-gp inhibition by tariquidar in wild-type, heterozygous Abcb1a/b (+/-) and homozygous Abcb1a/b (-/-) mice as models with controlled levels of cerebral P-gp expression. Brains were collected to quantify P-gp expression with immunohistochemistry. Brain uptake of [ 11 C]metoclopramide was expressed as the area under the brain time-activity curve (AUC brain ) and compared with data previously obtained with ( R )-[ 11 C]verapamil and [ 11 C] N -desmethyl-loperamide. Abcb1a/b (+/-) mice had intermediate P-gp expression compared to wild-type and Abcb1a/b (-/-) mice. In baseline scans, all three radiotracers were able to discriminate Abcb1a/b (-/-) from wild-type mice (2.5- to 4.6-fold increased AUC brain , p ≤ 0.0001). However, only [ 11 C]metoclopramide could discriminate Abcb1a/b (+/-) from wild-type mice (1.46-fold increased AUC brain , p ≤ 0.001). After partial P-gp inhibition, differences in [ 11 C]metoclopramide AUC brain between Abcb1a/b (+/-) and wild-type mice (1.39-fold, p ≤ 0.001) remained comparable to baseline. There was a negative correlation between baseline [ 11 C]metoclopramide AUC brain and ex-vivo -measured P-gp immunofluorescence (r =  - 0.9875, p ≤ 0.0001). Our data suggest that [ 11 C]metoclopramide is a sensitive radiotracer to measure moderate, but (patho-)physiologically relevant decreases in cerebral P-gp function without the need to co-administer a P-gp inhibitor., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In the lungs, the membrane transporter P-glycoprotein (P-gp) is expressed in the apical (i.e. lumen-facing) membrane of airway epithelial cells and in the luminal (blood-facing) membrane of pulmonary capillary endothelial cells. To better understand the influence of P-gp on the pulmonary disposition of inhaled P-gp substrate drugs, we measured the intrapulmonary pharmacokinetics of the intratracheally (i.t.) aerosolized model P-gp substrate [ 11 C]metoclopramide in presence and absence of P-gp activity by means of positron emission tomography (PET) imaging in rats. Data were compared to data previously acquired with the model P-gp substrates (R)-[ 11 C]verapamil and [ 11 C]N-desmethyl-loperamide, using the same experimental set-up. Groups of wild-type rats, either untreated or treated with the P-gp inhibitor tariquidar, and Abcb1a/b (-/-) rats underwent 90-min dynamic PET scans after i.t. aerosolization of [ 11 C]metoclopramide. Lung exposure to [ 11 C]metoclopramide was expressed as the area under the right lung concentration-time curve (AUC lung ). AUC lung values were significantly higher in Abcb1a/b (-/-) rats (1.8-fold, p ≤ 0.0001) and in tariquidar-treated wild-type rats (1.6-fold, p ≤ 0.01) than in untreated wild-type rats. This differed from previously obtained results with (R)-[ 11 C]verapamil and [ 11 C]N-desmethyl-loperamide, which showed decreased exposure in the rat lung in absence of P-gp activity. Our results suggest that transepithelial transfer of [ 11 C]metoclopramide was not or only to a small extent affected by P-gp activity, presumably due to the compound's high passive permeability. The increased lung retention of [ 11 C]metoclopramide may be due to decreased P-gp-mediated clearance into the blood in absence of P-gp activity in capillary endothelial cells. The overall effect of P-gp on the lung exposure to inhaled P-gp substrate drugs may, thus, be determined by a balance of opposing effects at the pulmonary epithelium and endothelium., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Transporter-mediated drug-drug interactions (DDIs) are of concern in antimicrobial drug development, as they can have serious safety consequences. We used positron emission tomography (PET) imaging-based pharmacokinetic (PK) analysis to assess the effect of different drugs, which may cause transporter-mediated DDIs, on the tissue distribution and excretion of [ 18 F]ciprofloxacin as a radiolabeled model antimicrobial drug. Mice underwent PET scans after intravenous injection of [ 18 F]ciprofloxacin, without and with pretreatment with either probenecid (150 mg/kg), cimetidine (50 mg/kg), or pyrimethamine (5 mg/kg). A 3-compartment kidney PK model was used to assess the involvement of renal transporters in the examined DDIs. Pretreatment with probenecid and cimetidine significantly decreased the renal clearance (CL renal ) of [ 18 F]ciprofloxacin. The effect of cimetidine (-86%) was greater than that of probenecid (-63%), which contrasted with previously published clinical data. The kidney PK model revealed that the decrease in CL renal was caused by inhibition of basal uptake transporters and apical efflux transporters in kidney proximal tubule cells. Changes in the urinary excretion of [ 18 F]ciprofloxacin after pretreatment with probenecid and cimetidine resulted in increased blood and organ exposure to [ 18 F]ciprofloxacin. Our results suggest that multiple membrane transporters mediate the tubular secretion of ciprofloxacin, with possible species differences between mice and humans. Concomitant medication inhibiting renal transporters may precipitate DDIs, leading to decreased urinary excretion and increased blood and organ exposure to ciprofloxacin, potentially exacerbating adverse effects. Our study highlights the strength of PET imaging-based PK analysis to assess transporter-mediated DDIs at a whole-body level.

PURPOSE OF THE STUDY Tranexamic acid as a haemostatic agent is commonly used in multiple medical branches. Over the last decade, there has been a steep rise in the number of studies evaluating its effect, i.e. blood loss reduction in specific surgical procedures. The aim of our study was to evaluate the effect of tranexamic acid on reducing intraoperative blood loss, postoperative blood loss into the drain, total blood loss, transfusion requirements, and development of symptomatic wound hematoma in conventional single-level lumbar decompression and stabilization. MATERIAL AND METHODS The study included patients who had undergone a traditional open lumbar spine surgery in the form of single-level decompression and stabilisation. The patients were randomized into two groups. The study group received a 15 mg/kg dose of tranexamic acid intravenously during the induction of anaesthesia and then again 6 hours later. No tranexamic acid was administered to the control group. In all patients, intraoperative blood loss, postoperative blood loss into the drain, and therefore also total blood loss, transfusion requirements and potential development of a symptomatic postoperative wound hematoma requiring surgical evacuation were recorded. The data of the two groups were compared. RESULTS The cohort includes 162 patients, 81 in the study group and the same number in the control group. In the intraoperative blood loss assessment, no statistically significant difference between the two groups was observed; 430 (190-910) mL vs. 435 (200-900) mL. In case of post-operative drain blood loss, a statistically significantly lower volume was reported after the tranexamic acid administration; 405 (180-750) mL vs. 490 (210-820) mL. When evaluating the total blood loss, a statistically significant difference was also confirmed, namely in favour of the tranexamic acid; 860 (470-1410) mL vs. 910 (500- 1420) mL. The reduction of total blood loss did not result in a difference in the number of administered transfusions; transfusions were given to 4 patients in each group. A postoperative wound hematoma requiring surgical evacuation developed in 1 patient in the group with the tranexamic acid and in 4 patients in the control group, but the difference was not statistically significant with respect to the insufficient group size. No patient in our study experienced complications associated with tranexamic acid application. DISCUSSION The beneficial effect of tranexamic acid on reducing blood loss in lumbar spine surgeries has already been confirmed by numerous meta-analyses. The question remains in what types of procedures, at what dose and route of administration its effect is significant. To date, most of the studies have explored its effect in multi-level decompressions and stabilizations. Raksakietisak et al., for instance, report significant reduction in total blood loss from 900 (160, 4150) mL to 600 (200, 4750) mL following an intravenous injection of 2 bolus doses of 15 mg/kg tranexamic acid. In less extensive spinal surgeries, the effect of tranexamic acid may not be that distinct. In our study of single-level decompressions and stabilizations, no reduction in the actual intraoperative bleeding was confirmed at the given dosage. Its effect was seen only in the postoperative period in a significant reduction of blood loss into the drain, thus also in the total blood loss, although the difference between 910 (500, 1420) mL and 860 (470, 1410) mL was not that significant. CONCLUSIONS By intravenous application of tranexamic acid in 2 bolus doses in single-level decompression and stabilization of the lumbar spine a statistically significant reduction in postoperative blood loss into the drain and also total blood loss was confirmed. The reduction in the actual intraoperative blood loss was not statistically significant. No difference was observed in the number of administered transfusions. Following the tranexamic acid administration, a lower number of postoperative symptomatic wound hematomas was recorded, but the difference was not statistically significant. Key words: tranexamic acid, spinal surgeries, blood loss, postoperative hematoma.

Purpose: Nanodiamonds (NDs) represent a new class of nanoparticles and have gained increasing interest in medical applications. Modifying the surface coating by attaching binding ligands or imaging probes can transform NDs into multi-modal targeting probes. This study evaluated the biokinetics and biodistribution of 68 Ga-radiolabelled NDs in a xenograft model., Procedures: NDs were coated with an albumin-derived copolymer modified with desferrioxamine to provide a chelator for radiolabeling. In vivo studies were conducted in AR42J tumor-bearing CD1 mice to evaluate biodistribution and tumor accumulation of the NDs., Results: Coated NDs were successfully radiolabeled using 68 Ga at room temperature with radiolabeling efficiencies up to 91.8 ± 3.2 % as assessed by radio-TLC. In vivo studies revealed the highest accumulation in the liver and spleen, whereas tumor radioactivity concentration was low., Conclusions: Radiolabeling of coated NDs could be achieved. However, the obtained results indicate these coated NDs' limitations in their biodistribution within the conducted studies., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. Increased expression of CXCR4 has been associated with liver metastasis, disease progression, and shortened survival. Using in vitro cell binding studies and the in ovo model, we aimed to investigate the potential of [ 68 Ga]Ga-Pentixafor, a radiotracer specifically targeting human CXCR4, for CRC imaging. Specific membrane binding and internalisation of [ 68 Ga]Ga-Pentixafor was shown for HT29 cells, but not for HCT116 cells. Accordingly, [ 68 Ga]Ga-Pentixafor accumulated specifically in CAM-xenografts derived from HT29 cells, but not in HCT116 xenografts, as determined by µPET/MRI. The CAM-grown xenografts were histologically characterised, demonstrating vascularisation of the graft, preserved expression of human CXCR4, and viability of the tumour cells within the grafts. In vivo viability was further confirmed by µPET/MRI measurements using 2-[ 18 F]FDG as a surrogate for glucose metabolism. [ 68 Ga]Ga-Pentixafor µPET/MRI scans showed distinct radiotracer accumulation in the chick embryonal heart, liver, and kidneys, whereas 2-[ 18 F]FDG uptake was predominantly found in the kidneys and joints of the chick embryos. Our findings suggest that [ 68 Ga]Ga-Pentixafor is an interesting novel radiotracer for CRC imaging that is worth further investigation. Moreover, this study further supports the suitability of the CAM-xenograft model for the initial preclinical evaluation of targeted radiopharmaceuticals.

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two efflux transporters which are expressed in the apical (i.e. airway lumen-facing) membranes of lung epithelial cells. To assess the influence of P-gp and BCRP on the pulmonary disposition of inhaled drugs, we performed positron emission tomography (PET) imaging in rats after intratracheal aerosolization of two model P-gp/BCRP substrate radiotracers (i.e. [ 11 C]erlotinib and [ 11 C]tariquidar). We studied rat groups in which both transporters were active (i.e. wild-type rats), either of the two transporters was inactive (Abcb1a/b (-/-) and Abcg2 (-/-) rats) or both transporters were inactive (Abcg2 (-/-) rats in which pulmonary P-gp activity was inhibited by treatment with unlabeled tariquidar). PET-measured lung distribution data were compared with brain-to-plasma radioactivity concentration ratios measured in a gamma counter at the end of the PET scan. For [ 11 C]erlotinib, lung exposure (AUC lungs ) was moderately but not significantly increased in Abcb1a/b (-/-) rats (1.6-fold) and Abcg2 (-/-) rats (1.5-fold), and markedly (3.6-fold, p < 0.0001) increased in tariquidar-treated Abcg2 (-/-) rats, compared to wild-type rats. Similarly, the brain uptake of [ 11 C]erlotinib was substantially (4.5-fold, p < 0.0001) increased when both P-gp and BCRP activities were impaired. For [ 11 C]tariquidar, differences in AUC lungs between groups pointed into a similar direction as for [ 11 C]erlotinib, but were less pronounced and lacked statistical significance. Our study demonstrates functional P-gp and BCRP activity in vivo in the lungs and further suggests functional redundancy between P-gp and BCRP in limiting the pulmonary uptake of a model P-gp/BCRP substrate, analogous to the blood-brain barrier. Our results suggest that pulmonary efflux transporters are important for the efficacy and safety of inhaled drugs and that their modulation may be exploited in order to improve the pharmacokinetic and pharmacodynamic performance of pulmonary delivered drugs., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Multidrug resistance-associated protein 1 (MRP1, encoded by the ABCC1 gene) may contribute to the clearance of amyloid-beta (Aβ) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aβ clearance. In this study, we assessed the effect of thiethylperazine, an antiemetic drug which was shown to stimulate MRP1 activity in vitro and to decrease Aβ load in a rapid β-amyloidosis mouse model (APP/PS1-21), on MRP1 transport activity by means of positron emission tomography (PET) imaging with the MRP1 tracer 6-bromo-7-[ 11 C]methylpurine. Groups of wild-type, APP/PS1-21 and Abcc1 (-/-) mice underwent PET scans before and after a 5-day oral treatment period with thiethylperazine (15 mg/kg, once daily). The elimination rate constant of radioactivity ( k elim ) was calculated from time-activity curves in the brain and the lungs as a measure of tissue MRP1 activity. Treatment with thiethylperazine had no significant effect on MRP1 activity in the brain and the lungs of wild-type and APP/PS1-21 mice. This may either be related to a lack of an MRP1-stimulating effect of thiethylperazine in vivo or to other factors, such as substrate-dependent MRP1 stimulation, insufficient target tissue exposure to thiethylperazine or limited sensitivity of the PET tracer to measure MRP1 stimulation.

Several drugs approved for inhalation for the treatment of pulmonary diseases are substrates of the adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (P-gp). P-gp is expressed in the apical membrane of pulmonary epithelial cells and could play a role in modulating the pulmonary absorption and distribution of inhaled drugs, thereby potentially contributing to variability in therapeutic response and/or systemic side effects. We developed a new in vivo experimental approach to assess the functional impact of P-gp on the pulmonary delivery of inhaled drugs in rats. By using positron emission tomography (PET) imaging, we measured the intrapulmonary pharmacokinetics of the model P-gp substrates (R)-[ 11 C]verapamil ([ 11 C]VPM) and [ 11 C]-N-desmethyl-loperamide ([ 11 C]dLOP) administered by intratracheal aerosolization in three rat groups: wild-type, Abcb1a/b (-/-) and wild-type treated with the P-gp inhibitor tariquidar. Lung exposure (AUC lung&#95;right ) to [ 11 C]VPM was 64% and 50% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b (-/-) rats, respectively, compared to untreated wild-type rats. For [ 11 C]dLOP, AUC lung&#95;right was 59% and 34% lower (p < 0.05) in tariquidar-treated and in Abcb1a/b (-/-) rats, respectively. Our results show that P-gp can affect the pulmonary disposition of inhaled P-gp substrates, whereby a decrease in P-gp activity may lead to lower lung exposure and potentially to a decrease in therapeutic efficacy. Our study highlights the potential of PET imaging with intratracheally aerosolized radiotracers to assess the impact of membrane transporters on pulmonary drug delivery, in rodents and potentially also in humans., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: To better understand the etiology and pathomechanisms of Alzheimer's disease, several transgenic animal models that overexpress human tau or human amyloid-beta (Aβ) have been developed. In the present study, we generated a novel transgenic rat model by cross-breeding amyloid precursor protein (APP) rats with tau rats. We characterized this model by performing positron emission tomography scans combined with immunofluorescent labeling and cerebrospinal fluid analyses., Methods: APP/Tau rats were generated by cross-breeding male McGill-R-Thy1-APP transgenic rats with female hTau-40/P301L transgenic rats. APP/Tau double transgenic rats and non-transgenic (ntg) littermates aged 7, 13, and 21 months were subjected to dynamic [ 11 C] PiB scan and dynamic [ 18 F]THK-5317 scans. For regional brain analysis, a template was generated from anatomical MR images of selected animals, which was co-registered with the PET images. Regional analysis was performed by application of the simplified reference tissue model ([ 11 C]PiB data), whereas [ 18 F]THK-5317 data were analyzed using a 2-tissue compartment model and Logan graphical analysis. In addition, immunofluorescent labeling (tau, amyloid) and cerebrospinal fluid analyses were performed., Results: [ 11 C]PiB binding potential (BP ND ) and [ 18 F]THK-5317 volume of distribution (V T ) showed an increase with age in several brain regions in the APP/Tau group but not in the ntg control group. Immunohistochemical analysis of brain slices of PET-scanned animals revealed a positive correlation between Aβ labeling and [ 11 C]PiB regional BP ND . Tau staining yielded a trend towards higher levels in the cortex and hippocampus of APP/Tau rats compared with ntg littermates, but without reaching statistical significance. No correlation was found between tau immunofluorescence labeling results and the respective [ 18 F]THK-5317 V T values., Conclusions: We thoroughly characterized a novel APP/Tau rat model using combined PET imaging and immunofluorescence analysis. We observed an age-related increase in [ 11 C]PiB and [ 18 F]THK-5317 binding in several brain regions in the APP/Tau group but not in the ntg group. Although we were able to reveal a positive correlation between amyloid labeling and [ 11 C]PiB regional brain uptake, we observed relatively low human tau and amyloid fibril expression levels and a somewhat unstable brain pathology which questions the utility of this animal model for further studies., (© 2021. The Author(s).)

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are co-localized at the blood-brain barrier, where they display functional redundancy to restrict the brain distribution of dual P-gp/BCRP substrate drugs. We used positron emission tomography (PET) with the metabolically stable P-gp/BCRP substrates [ 11 C]tariquidar, [ 11 C]erlotinib, and [ 11 C]elacridar to assess whether a similar functional redundancy as at the BBB exists in the liver, where both transporters mediate the biliary excretion of drugs. Wild-type, Abcb1a/b (-/-) , Abcg2 (-/-) , and Abcb1a/b (-/-) Abcg2 (-/-) mice underwent dynamic whole-body PET scans after i.v. injection of either [ 11 C]tariquidar, [ 11 C]erlotinib, or [ 11 C]elacridar. Brain uptake of all three radiotracers was markedly higher in Abcb1a/b (-/-) Abcg2 (-/-) mice than in wild-type mice, while only moderately changed in Abcb1a/b (-/-) and Abcg2 (-/-) mice. The transfer of radioactivity from liver to excreted bile was significantly lower in Abcb1a/b (-/-) Abcg2 (-/-) mice and almost unchanged in Abcb1a/b (-/-) and Abcg2 (-/-) mice (with the exception of [ 11 C]erlotinib, for which biliary excretion was also significantly reduced in Abcg2 (-/-) mice). Our data provide evidence for redundancy between P-gp and BCRP in controlling both the brain distribution and biliary excretion of dual P-gp/BCRP substrates and highlight the utility of PET as an upcoming tool to assess the effect of transporters on drug disposition at a whole-body level.

Ciprofloxacin is a commonly prescribed fluoroquinolone antibiotic which is cleared by active tubular secretion and intestinal excretion. Ciprofloxacin is a known substrate of the ATP-binding cassette (ABC) transporters breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 4 (MRP4). In this work, we used positron emission tomography (PET) imaging to investigate the influence of BCRP, MRP4, MRP2 and P-glycoprotein (P-gp) on the excretion of [ 18 F]ciprofloxacin in mice. Dynamic 90-min PET scans were performed after intravenous injection of [ 18 F]ciprofloxacin in wild-type mice without and with pre-treatment with the broad-spectrum MRP inhibitor MK571. Moreover, [ 18 F]ciprofloxacin PET scans were performed in Abcc4 (-/-) , Abcc2 (-/-) , Abcc4 (-/-) Abcg2 (-/-) and Abcb1a/b (-/-) Abcg2 (-/-) mice. In addition to non-compartmental pharmacokinetic (PK) analysis, a novel three-compartment PK model was developed for a detailed assessment of the renal disposition of [ 18 F]ciprofloxacin. In MK571 pre-treated mice, a significant increase in the blood exposure to [ 18 F]ciprofloxacin was observed along with a significant reduction in the renal and intestinal clearances. PK modelling revealed a significant reduction in renal radioactivity uptake (CL 1 ) and in the rate constants for transfer of radioactivity from the corticomedullary renal region into blood (k 2 ) and urine (k 3 ), respectively, after MK571 administration. No changes in the renal clearance or in the estimated kidney PK model parameters were observed in any of the studied knockout models, while a significant reduction in the intestinal clearance was observed in Abcc2 (-/-) and Abcc4 (-/-) Abcg2 (-/-) mice. Our data failed to reveal a role of any of the studied ABC transporters in the tubular secretion of ciprofloxacin. This may indicate that ciprofloxacin is handled in the kidneys by more than one transporter family, most likely with a great degree of mutual functional redundancy. Our study highlights the potential of PET imaging for an assessment of transporter-mediated renal excretion of radiolabelled drugs., (Copyright © 2021. Published by Elsevier B.V.)