Three-compartment pharmacokinetic models of radiotracers used in the GFR-determination — estimation of their parameters using the time-concentration curves

BACKGROUND: In GFR measurements with radiotracers, there is evidence that a two-compartment model is unable to describe the full plasma curve, including early time points, but analyses generally focus on two-compartment models. AIMS: To analyze both the mammillary and catenary three-compartment model and to determine empirical relations between model constants and the overall GFR and ECV (extra-cellular volume). MATERIAL AND METHODS: Mathematical analysis of the three-compartment model. Full-curve patient data from 32 adults and 7 children were used to relate model parameters to GFR and ECV. RESULTS: Model volumes were found to be roughly proportional to ECV. In both models, the central (plasma) volume was V1 = 0.24 × ECV and elimination rate from V1 was k10 = 4.2 × GFR/ECV. In the mammillary model, the two parallel volumes were V2 = 0.28 × ECV, V3 = 0.48 × ECV, and intercompartmental clearances were Cl12 [mL/min] = 0.0058 × ECV [mL], Cl13 = 0.042 × ECV. In the catenary model, the serial volumes were V2 = 0.60 × ECV, V3 = 0.16 × ECV, with clearances Cl12 = 0.048 × ECV, Cl23 = 0.0036 × ECV. CONCLUSION: Insight into the three-compartment model was achieved, and empirical relations to ECV and GFR/ECV were determined

Radiotracers for Bone Marrow Infection Imaging

Introduction: Radiotracers are widely used in medical imaging, using techniques of gamma-camera imaging (scintigraphy and SPECT) or positron emission tomography (PET). In bone marrow infection, there is no single routine test available that can detect infection with sufficiently high diagnostic accuracy. Here, we review radiotracers used for imaging of bone marrow infection, also known as osteomyelitis, with a focus on why these molecules are relevant for the task, based on their physiological uptake mechanisms. The review comprises [(67)Ga]Ga-citrate, radiolabelled leukocytes, radiolabelled nanocolloids (bone marrow) and radiolabelled phosphonates (bone structure), and [(18)F]FDG as established radiotracers for bone marrow infection imaging. Tracers that are under development or testing for this purpose include [(68)Ga]Ga-citrate, [(18)F]FDG, [(18)F]FDS and other non-glucose sugar analogues, [(15)O]water, [(11)C]methionine, [(11)C]donepezil, [(99m)Tc]Tc-IL-8, [(68)Ga]Ga-Siglec-9, phage-display selected peptides, and the antimicrobial peptide [(99m)Tc]Tc-UBI(29-41) or [(68)Ga]Ga-NOTA-UBI(29-41). Conclusion: Molecular radiotracers allow studies of physiological processes such as infection. None of the reviewed molecules are ideal for the imaging of infections, whether bone marrow or otherwise, but each can give information about a separate aspect such as physiology or biochemistry. Knowledge of uptake mechanisms, pitfalls, and challenges is useful in both the use and development of medically relevant radioactive tracers

Preclinical Testing of Radiopharmaceuticals for the Detection and Characterization of Osteomyelitis:Experiences from a Porcine Model

The development of new and better radioactive tracers capable of detecting and characterizing osteomyelitis is an ongoing process, mainly because available tracers lack selectivity towards osteomyelitis. An integrated part of developing new tracers is the performance of in vivo tests using appropriate animal models. The available animal models for osteomyelitis are also far from ideal. Therefore, developing improved animal osteomyelitis models is as important as developing new radioactive tracers. We recently published a review on radioactive tracers. In this review, we only present and discuss osteomyelitis models. Three ethical aspects (3R) are essential when exposing experimental animals to infections. Thus, we should perform experiments in vitro rather than in vivo (Replacement), use as few animals as possible (Reduction), and impose as little pain on the animal as possible (Refinement). The gain for humans should by far exceed the disadvantages for the individual experimental animal. To this end, the translational value of animal experiments is crucial. We therefore need a robust and well-characterized animal model to evaluate new osteomyelitis tracers to be sure that unpredicted variation in the animal model does not lead to a misinterpretation of the tracer behavior. In this review, we focus on how the development of radioactive tracers relies heavily on the selection of a reliable animal model, and we base the discussions on our own experience with a porcine model

Absorption rate of subcutaneously infused fluid in ill multimorbid older patients

BACKGROUND: Subcutaneous (SC) hydration is a valuable method for treating dehydration in the very old patients. Data are absent on the absorption rate, and the availability of SC infused fluid in the circulation in this group of patients where SC hydration is particularly relevant. METHODS: We performed an explorative study on ill very old (range 78–84 years old) geriatric patients with comorbidities who received an SC infusion of 235 ml isotonic saline containing a technetium-99m pertechnetate tracer. The activity over the infusion site was measured using a gamma detector to assess the absorption rate from the SC space. The activity was measured initially every 5 minutes, with intervals extended gradually to 15 minutes. Activity in blood samples and the thyroid gland was measured to determine the rate of availability in the circulation. RESULTS: Six patients were included. The mean age was 81 years (SD 2.1), the number of comorbidities was 4.6 (SD 1.3), and the Tilburg frailty indicator was 3.8 (SD 2.4). When the infusion was completed after 60 minutes, 53% (95% CI 50–56%) of the infused fluid was absorbed from the SC space, with 88% (95% CI 86–90%) absorbed one hour later. The absorption rate from the SC space right after the completion of the infusion was 127 ml/h (95% CI 90–164 ml/h). The appearance of the fluid into the blood and the thyroid gland verified the transfer from SC to circulation. CONCLUSION: This first explorative study of absorption of SC infused fluid in the very old found an acceptable amount of fluid absorbed from the SC space into the circulation one hour after infusion had ended. Results are uniform but should be interpreted cautiously due to the low sample size. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04536324

Lymph Nodes Draining Infections Investigated by PET and Immunohistochemistry in a Juvenile Porcine Model

Background: [(18)F]FDG and [(11)C]methionine accumulate in lymph nodes draining S. aureus -infected foci. The lymph nodes were characterized by weight, [(11)C]methionine- and [(18)F]FDG-positron emissions tomography (PET)/computed tomography (CT), and immunohistochemical (IHC)-staining. Methods: 20 pigs inoculated with S. aureus into the right femoral artery were PET/CT-scanned with [(18)F]FDG, and nine of the pigs were additionally scanned with [(11)C]methionine. Mammary, medial iliac, and popliteal lymph nodes from the left and right hind limbs were weighed. IHC-staining for calculations of area fractions of Ki-67, L1, and IL-8 positive cells was done in mammary and popliteal lymph nodes from the nine pigs. Results: The pigs developed one to six osteomyelitis foci. Some pigs developed contiguous infections of peri-osseous tissue and inoculation-site abscesses. Weights of mammary and medial iliac lymph nodes and their [(18)F]FDG maximum Standardized Uptake Values (SUV(FDGmax)) showed a significant increase in the inoculated limb compared to the left limb. Popliteal lymph node weight and their FDG uptake did not differ significantly between hind limbs. Area fractions of Ki-67 and IL-8 in the right mammary lymph nodes and SUV(Metmax) in the right popliteal lymph nodes were significantly increased compared with the left side. Conclusion: The PET-tracers [(18)F]FDG and [(11)C]methionine, and the IHC- markers Ki-67 and IL-8, but not L1, showed increased values in lymph nodes draining soft tissues infected with S. aureus. The increase in [(11)C]methionine may indicate a more acute lymph node response, whereas an increase in [(18)F]FDG may indicate a more chronic response

Kinetic Modelling of [⁶⁸Ga]Ga-DOTA-Siglec-9 in Porcine Osteomyelitis and Soft Tissue Infections

Background: [68Ga]Ga-DOTA-Siglec-9 is a positron emission tomography (PET) radioligand for vascular adhesion protein 1 (VAP-1), a protein involved in leukocyte trafficking. The tracer facilitates the imaging of inflammation and infection. Here, we studied the pharmacokinetic modelling of [68Ga]Ga-DOTA-Siglec-9 in osteomyelitis and soft tissue infections in pigs. Methods: Eight pigs with osteomyelitis and soft tissue infections in the right hind limb were dynamically PET scanned for 60 min along with arterial blood sampling. The fraction of radioactivity in the blood accounted for by the parent tracer was evaluated with radio-high-performance liquid chromatography. One- and two-tissue compartment models were used for pharmacokinetic evaluation. Post-mortem soft tissue samples from one pig were analysed with anti-VAP-1 immunofluorescence. In each analysis, the animal’s non-infected left hind limb was used as a control. Results: Tracer uptake was elevated in soft tissue infections but remained low in osteomyelitis. The kinetics of [68Ga]Ga-DOTA-Siglec-9 followed a reversible 2-tissue compartment model. The tracer metabolized quickly; however, taking this into account, produced more ambiguous results. Infected soft tissue samples showed endothelial cell surface expression of the Siglec-9 receptor VAP-1. Conclusion: The kinetics of [68Ga]Ga-DOTA-Siglec-9 uptake in porcine soft tissue infections are best described by the 2-tissue compartment model

Kinetic Modelling of Infection Tracers [ 18

Introduction. Positron emission tomography (PET) is increasingly applied for infection imaging using [18F]FDG as tracer, but uptake is unspecific. The present study compares the kinetics of [18F]FDG and three other PET tracers with relevance for infection imaging. Methods. A juvenile porcine osteomyelitis model was used. Eleven pigs underwent PET/CT with 60-minute dynamic PET imaging of [18F]FDG, [68Ga]Ga-citrate, [11C]methionine, and/or [11C]donepezil, along with blood sampling. For infectious lesions, kinetic modelling with one- and two-tissue-compartment models was conducted for each tracer. Results. Irreversible uptake was found for [18F]FDG and [68Ga]Ga-citrate; reversible uptake was found for [11C]methionine (two-tissue model) and [11C]donepezil (one-tissue model). The uptake rate for [68Ga]Ga-citrate was slow and diffusion-limited. For the other tracers, the uptake rate was primarily determined by perfusion (flow-limited uptake). Net uptake rate for [18F]FDG and distribution volume for [11C]methionine were significantly higher for infectious lesions than for correspondingly noninfected tissue. For [11C]donepezil in pigs, labelled metabolite products appeared to be important for the analysis. Conclusions. The kinetics of the four studied tracers in infection was characterized. For clinical applications, [18F]FDG remains the first-choice PET tracer. [11C]methionine may have a potential for detecting soft tissue infections. [68Ga]Ga-citrate and [11C]donepezil were not found useful for imaging of osteomyelitis