Arterial Time-activity Curve Research Articles

Pharmacokinetic Comparison of Selective Prostatic Arterial and Intravenous PSMA PET/CT Radioligand Infusions in Primary Prostatic Adenocarcinoma.

Background Intravenous prostate-specific membrane antigen (PSMA)-targeted radioligand therapy improves survival in men with metastatic castration-resistant prostate cancer. Yet, the impact of selective prostatic arterial administration on primary tumor uptake is unclear. Purpose To compare gallium 68 (68Ga)-PSMA-11 uptake using dynamic PET/CT in prostatic tumoral volumes of interest (VOIs) during intravenous and selective prostatic arterial infusions for individuals with untreated, high-risk prostate cancer. Materials and Methods In this prospective, intraindividual comparative study conducted at an academic medical center, five men aged 58, 61, 64, 66, and 68 years with treatment-naive prostate cancer were enrolled between January 2022 and February 2023 and underwent two dynamic 68Ga-PSMA-11 PET/CT examinations 1 week apart. During the first examination, the radiotracer was administered intravenously. During the second administration, the radiotracer was delivered into either the right or left prostatic artery through an angiographically placed microcatheter. The primary outcome was maximum standardized uptake value (SUVmax) in prostatic tumoral VOIs. The secondary outcomes included mean SUV (SUVmean) in prostatic tumoral VOIs and area under the SUVmean curves (AUC). Longitudinal mixed-effects models were used to compare dynamic SUVmax and SUVmean time-activity curves (TACs), and paired t tests were used for the remaining data. Results The mean SUVmax within tumoral VOIs was 14 (range, 3-43) for venous sessions and 938 (range, 460-1436) for arterial sessions (P = .008). The SUVmean within VOIs was greater during arterial sessions (P < .001) overall and 46-fold and 19-fold greater at peak uptake and final time points, respectively. The mean AUC was greater on arterial TACs than on venous TACs at 14600 SUV × min (range, 8353-20025 SUV × min) and 240 SUV × min (range, 69-622 SUV × min), respectively (P = .002). Conclusion Selective prostatic arterial infusion resulted in greater 68Ga-PSMA-11 tumoral SUV than intravenous infusion. Further study of local-regional, intra-arterial delivery of a PSMA-targeted theranostic agent is warranted in high-risk prostate cancer. ClinicalTrials.gov identifier: NCT04976257 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Civelek in this issue.

Pharmacokinetic Evaluation of New Drugs Using a Multi-Labelling Approach and PET Imaging: Application to a Drug Candidate with Potential Application in Neuromuscular Disorders.

The determination of pharmacokinetic properties of new chemical entities is a key step in the process of drug development. Positron emission tomography (PET) is an ideal technique to obtain both biodistribution and pharmacokinetic parameters of new compounds over a wide range of chemical modalities. Here, we use a multi-radionuclide/multi-position labelling approach to investigate distribution, elimination, and metabolism of a triazole-based FKBP12 ligand (AHK2) with potential application in neuromuscular disorders. Target engagement and stabilizing capacity of the drug candidate (AHK2) towards FKBP12-RyR was evaluated using competitive ligand binding and proximity ligation assays, respectively. Subsequently, AHK2 was labelled either with the positron emitter carbon-11 (11C) via 11C-methylation to yield both [11C]AHK2.1 and [11C]AHK2.2, or by palladium-catalysed reduction of the corresponding 5-iodotriazole derivative using 3H gas to yield [3H]AHK2. Metabolism was first investigated in vitro using liver microsomes. PET imaging studies in rats after intravenous (IV) administration at different doses (1 µg/Kg and 5 mg/Kg) were combined with determination of arterial blood time-activity curves (TACs) and analysis of plasma samples by high performance liquid chromatography (HPLC) to quantify radioactive metabolites. Arterial TACs were obtained in continuous mode by using an in-house developed system that enables extracorporeal blood circulation and continuous measurement of radioactivity in the blood. Pharmacokinetic parameters were determined by non-compartmental modelling of the TACs. In vitro studies indicate that AHK2 binds to FKBP12 at the rapamycin-binding pocket, presenting activity as a FKBP12/RyR stabilizer. [11C]AHK2.1, [11C]AHK2.2 and [3H]AHK2 could be obtained in overall non-decay corrected radiochemical yields of 14 ± 2%, 15 ± 2% and 0.05%, respectively. Molar activities were 60-110 GBq/µmol, 68-122 GBq/µmol and 0.4-0.5 GBq/μmol, respectively. In vitro results showed that oxidation of the thioether group into sulfoxide, demethylation of the CH3O-Ar residue and demethylation of -N(CH3)2 were the main metabolic pathways. Fast metabolism was observed in vivo. Pharmacokinetic parameters obtained from metabolite-corrected arterial blood TACs showed a short half-life (12.6 ± 3.3 min). Dynamic PET imaging showed elimination via urine when [11C]AHK2.2 was administered, probably reflecting the biodistribution of [11C]methanol as the major metabolite. Contrarily, accumulation in the gastrointestinal track was observed after administration of [11C]AKH2.1. AHK2 binds to FKBP12 at the rapamycin-binding pocket, presenting activity as a FKBP12/RyR stabilizer. Studies performed with the 3H- and 11C-labelled FKBP12/RyR stabilizer AHK2 confirm fast blood clearance, linear pharmacokinetics and rapid metabolism involving oxidation of the sulfide and amine moieties and oxidative demethylation of the CH3-O-Ar and tertiary amine groups as the main pathways. PET studies suggest that knowledge about metabolic pathways is paramount to interpret images.

Simulating the effect of venous dispersion on distribution volume measurements from the Logan plot

Measurement of distribution volume with the Logan plot requires an arterial time activity curve (TAC). The gold standard for measuring arterial activity concentrations is arterial blood sampling. Arterial cannulation carries with it several risks. This work simulated the effects of venous dispersion on measured distribution volumes using the Logan plot with a venous TAC. A representative arterial TAC was selected from a patient study. Simulated tissue TACs were generated from a three compartment kinetic model using the representative arterial TAC. Venous TACs were simulated by convolving the arterial TAC with modified transit time spectra derived from an in vivo dynamic contrast enhanced-CT forearm study. Gaussian noise was added to the tissue TACs. Logan analysis was compared using the arterial and venous TACs for a wide range of kinetic parameters. Bland–Altman analysis was performed to assess agreement between the two methods. Good agreement was observed between values calculated with the arterial and simulated venous TACs for both noiseless and noisy cases. Agreement was slightly dependent on the arterio–venous extraction efficiency of the PET tracer. Results suggest that venous sampling may be a feasible alternative to arterial sampling for analysis with the Logan plot. This technique must be clinically validated in future patient studies.

Abstract WP47: Flow Phantom for the Validation and Quantitative Analysis of Computed Tomography Perfusion

Objective: We create a flow phantom using a simple brain model with well-defined flow behavior. This allows for the validation of CT perfusion (CTP), as CTP data can be compared with theoretical calculations and gold standard flow meter values. Our approach offers a calibration system for existing CTP scanners, facilitating the selection of optimal data processing algorithms and parameter settings. Methods: The phantom was built using 37 parallel glass capillary tubes of internal diameter 1.0 mm fixed with epoxy. Saline was pumped into the inlet portion of a Y-shaped tubing system with one inlet and two outlets. One Y outlet led to the phantom, which was in series with a flow meter. The other outlet flowed to a waste container. A contrast bolus was introduced at the Y inlet and perfusion imaging was performed with a Toshiba 320 slice Aquilion One scanner. Phantom flow rates of 3, 5, 7.5 and 20 mL/min were used. Time activity curves (TACs) were calculated by averaging along various phantom segments. Results: CBV could be accurately recovered for all flow levels but 3 mL/min. MTT values were slightly higher than expected. Compared to TACs at the base of the Y, TACS just prior to the phantom showed significant dispersion. MTT measured across the phantom for length of 4.1 cm (i.e. internal volume 1 mL) with a flow meter rate of 20 mL/min was 0.066 min, whereas 0.05 min was expected. However, the same measurement for a flow of 3 mL/min had an MTT of 0.32 min, close to the expected value of 0.33 min. Conclusions: We have developed a robust system for the analysis of CTP. CBV was accurate provided sufficient scan duration. MTT values were mildly exaggerated due to dispersion of the contrast bolus. This is analogous to measuring an early arterial TAC, such as the carotid TAC, when tissue segments are fed by smaller branches. This dispersion causes a lower bound for MTT, an effect that is greater at higher flows. Our system has the potential for the calibration and optimization of existing commercial CTP devices.

Separation of input function for rapid measurement of quantitative CMRO2 and CBF in a single PET scan with a dual tracer administration method

Cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF) and cerebral blood flow (CBF) images can be quantified using positron emission tomography (PET) by administrating 15O-labelled water (H152O) and oxygen (15O2). Conventionally, those images are measured with separate scans for three tracers C15O for CBV, H152O for CBF and 15O2 for CMRO2, and there are additional waiting times between the scans in order to minimize the influence of the radioactivity from the previous tracers, which results in a relatively long study period. We have proposed a dual tracer autoradiographic (DARG) approach (Kudomi et al 2005), which enabled us to measure CBF, OEF and CMRO2 rapidly by sequentially administrating H152O and 15O2 within a short time. Because quantitative CBF and CMRO2 values are sensitive to arterial input function, it is necessary to obtain accurate input function and a drawback of this approach is to require separation of the measured arterial blood time–activity curve (TAC) into pure water and oxygen input functions under the existence of residual radioactivity from the first injected tracer. For this separation, frequent manual sampling was required. The present paper describes two calculation methods: namely a linear and a model-based method, to separate the measured arterial TAC into its water and oxygen components. In order to validate these methods, we first generated a blood TAC for the DARG approach by combining the water and oxygen input functions obtained in a series of PET studies on normal human subjects. The combined data were then separated into water and oxygen components by the present methods. CBF and CMRO2 were calculated using those separated input functions and tissue TAC. The quantitative accuracy in the CBF and CMRO2 values by the DARG approach did not exceed the acceptable range, i.e., errors in those values were within 5%, when the area under the curve in the input function of the second tracer was larger than half of the first one. Bias and deviation in those values were also compatible to that of the conventional method, when noise was imposed on the arterial TAC. We concluded that the present calculation based methods could be of use for quantitatively calculating CBF and CMRO2 with the DARG approach.

Corrections of arterial input function for dynamic H215O PET to assess perfusion of pelvic tumours: arterial blood sampling versus image extraction

Assessment of perfusion with 15O-labelled water (H215O) requires measurement of the arterial input function (AIF). The arterial time activity curve (TAC) measured using the peripheral sampling scheme requires corrections for delay and dispersion. In this study, parametrizations with and without arterial spillover correction for fitting of the tissue curve are evaluated. Additionally, a completely noninvasive method for generation of the AIF from a dynamic positron emission tomography (PET) acquisition is applied to assess perfusion of pelvic tumours. This method uses a volume of interest (VOI) to extract the TAC from the femoral artery. The VOI TAC is corrected for spillover using a separate tissue TAC and for recovery by determining the recovery coefficient on a coregistered CT data set. The techniques were applied in five patients with pelvic tumours who underwent a total of 11 examinations. Delay and dispersion correction of the blood TAC without arterial spillover correction yielded in seven examinations solutions inconsistent with physiology. Correction of arterial spillover increased the fitting accuracy and yielded consistent results in all patients. Generation of an AIF from PET image data was investigated as an alternative to arterial blood sampling and was shown to have an intrinsic potential to determine the AIF noninvasively and reproducibly. The AIF extracted from a VOI in a dynamic PET scan was similar in shape to the blood AIF but yielded significantly higher tissue perfusion values (mean of 104.0 ± 52.0%) and lower partition coefficients (−31.6 ± 24.2%). The perfusion values and partition coefficients determined with the VOI technique have to be corrected in order to compare the results with those of studies using a blood AIF.

Graph-based Mumford-Shah segmentation of dynamic PET with application to input function estimation

A graph-theoretic three-dimensional (3-D) segmentation algorithm based on Mumford-Shah energy minimization is applied to the segmentation of brain /sup 18/F-fluoro-deoxyglucose (FDG) dynamic positron emission tomography data for the automated extraction of tissues with distinct time activity curves (TACs), and, in particular, extraction of the internal carotid arteries and venous sinuses for the noninvasive estimation of the input arterial TAC. Preprocessing by principal component analysis (PCA) and a Mahalanobis distance metric provide segmentation based on distinct TAC shape rather than simply activity levels. Evaluations on simulation and clinical FDG brain positron emission tomography (PET) studies demonstrate that differing tissue types can be accurately demarcated with superior performance to k-means clustering approaches, and, in particular, the internal carotids and venous sinuses can be robustly segmented in clinical brain dynamic PET datasets, allowing for the fully automatic noninvasive estimation of the arterial input curve.

Impulse-response function of splanchnic circulation with model-independent constraints: theory and experimental validation.

Modeling physiological processes using tracer kinetic methods requires knowledge of the time course of the tracer concentration in blood supplying the organ. For liver studies, however, inaccessibility of the portal vein makes direct measurement of the hepatic dual-input function impossible in humans. We want to develop a method to predict the portal venous time-activity curve from measurements of an arterial time-activity curve. An impulse-response function based on a continuous distribution of washout constants is developed and validated for the gut. Experiments with simultaneous blood sampling in aorta and portal vein were made in 13 anesthetized pigs following inhalation of intravascular [15O]CO or injections of diffusible 3-O-[11C]methylglucose (MG). The parameters of the impulse-response function have a physiological interpretation in terms of the distribution of washout constants and are mathematically equivalent to the mean transit time (T) and standard deviation of transit times. The results include estimates of mean transit times from the aorta to the portal vein in pigs: T = 0.35 +/- 0.05 min for CO and 1.7 +/- 0.1 min for MG. The prediction of the portal venous time-activity curve benefits from constraining the regression fits by parameters estimated independently. This is strong evidence for the physiological relevance of the impulse-response function, which includes asymptotically, and thereby justifies kinetically, a useful and simple power law. Similarity between our parameter estimates in pigs and parameter estimates in normal humans suggests that the proposed model can be adapted for use in humans.

Measurement of muscle protein synthesis by positron emission tomography with L-[methyl-11C]methionine: effects of transamination and transmethylation.

Positron emission tomography with L-[methyl-11C]methionine provides a measure of regional protein synthesis rate (PSR) in skeletal muscle. However, the validity of the method depends on incorporation of methionine into protein with minimal transamination, transmethylation, or both. To test directly these assumptions, uptake of L-[methyl-14C]methionine in skeletal muscle was measured in control and cycloheximide-treated rats. Normal and cycloheximide-treated rats (n = 8/group) were injected with 50 microCi of L-[methyl-14C]methionine and arterial blood sampled over 90 minutes. After killing, thigh muscle was homogenized, centrifuged, and treated with trichloroacetic acid. PSR from circulating methionine was estimated from trichloroacetic acid-precipitable radioactivity, arterial time-activity curves, and plasma methionine concentrations. In normal rats, approximately 70% of the tissue radioactivity was precipitated with trichloroacetic acid. In normal animals, PSR was 0.22 nmoles x min(-1) x g(-1), in excellent agreement with previous results. In the cycloheximide-treated group, PSR was 0.0032 nmoles x min(-1) x g(-1); approximately 98% reduction compared with controls. These studies support the hypothesis that L-[methyl-11(14C]methionine accumulates in skeletal muscle as 11(14)C-labeled protein.

A simple on-line arterial time-activity curve detector for [O-15] water PET studies

A simple, automated on-line detector system has been fabricated and implemented to detect the arterial time-activity curve (TAG) for bolus-injection [O-15] water PET studies. This system offers two significant improvements over existing systems: a pump mechanism is not required to control arterial blood flow through the detector and dispersion correction of the time-activity curve for dispersion in external tubing is unnecessary. The [O-15] positrons emanating from blood within a thin-walled, 0.134 cm inner-diameter plastic tube are detected by a 0.5 cm wide by 1.0 cm long by 0.1 cm thick plastic scintillator mounted to a miniature PMT. Photon background is reduced to insignificant levels by a 2.0 cm thick cylindrical lead shield. Mean cerebral blood flow (mCBF) determined from an autoradiographic model and from the TAC measured by 1-second automated sampling was compared to that calculated from a TAC acquired using 5-second integrated manual samples. Improvements in timing resolution (1-sec vs. 5-sec) cause small but significant differences between the two sampling methods. Dispersion is minimized due to small tubing diameters, short lengths of tubing between the radial arterial sampling site and the detector and the presence of a 3-way valve 10 cm proximal to the detector.

A simple on-line arterial time-activity curve detector for ~O-15\ water PET studies

A simple, automated on-line detector system has been fabricated and implemented to detect the arterial time-activity curve (TAG) for bolus-injection ~O-15\ water PET studies. This system offers two significant improvements over existing systems: a pump mechanism is not required to control arterial blood flow through the detector and dispersion correction of the time-activity curve for dispersion in external tubing is unnecessary. The ~O-15\ positrons emanating from blood within a thin-walled, 0.134 cm inner-diameter plastic tube are detected by a 0.5 cm wide by 1.0 cm long by 0.1 cm thick plastic scintillator mounted to a miniature PMT. Photon background is reduced to insignificant levels by a 2.0 cm thick cylindrical lead shield. Mean cerebral blood flow (mCBF) determined from an autoradiographic model and from the TAC measured by 1-second automated sampling was compared to that calculated from a TAC acquired using 5-second integrated manual samples. Improvements in timing resolution (1-sec vs. 5-sec) cause small but significant differences between the two sampling methods. Dispersion is minimized due to small tubing diameters, short lengths of tubing between the radial arterial sampling site and the detector and the presence of a 3-way valve 10 cm proximal to the detector.

A method for biomedical system modelling and physiological parameter estimation using indirectly measured input functions

Tracer kinetic modelling with positron emission tomography (PET) requires measurements of the time-activity curves in both plasma (PTAC) and tissue (TTAC) to estimate physiological parameters, i.e. to fit the parameters of certain compartmental models using PTAC and TTAC as local tissue model input and output functions respectively. Ideally, this PTAC should be the local tracer capillary plasma time-activity curve (CPTAC). However, due to the inaccessibility of direct measurement of CPTAC from the capillary blood vessel, the tracer arterial plasma time-activity curve (APTAC) is normally used to replace CPTAC as PTAC. The physiological parameter estimation error caused by this replacement is not yet clear. In this paper, a PTAC model based on [18F] 2-fluoro-2-deoxy-D-glucose (FDG) experimental data is employed, in which CPTAC is the observable state variable. Therefore, the CPTAC time function can be constructed from the measured APTAC. This CPTAC is then used as the local input of a five-parameter FDG model, to study the effects of the replacement and APTAC measurement errors on the estimation of the FDG model's impulse response function parameters (macro-parameters), the rate constants (microparameters) and the physiological parameter-local cerebral metabolic rate of glucose (LCMRGlc). The results show that using APTAC directly in parameter estimation can cause considerable biases and increase the uncertainty of parameter estimation. The technique used in this paper to construct a tracer capillary plasma time-activity curve from the measured noisy arterial time-activity curve provides a general approach to measure the inaccessible true input function indirectly in biomedical systems and, therefore, to improve the physiological parameter estimation reliability

Measurement of arterial time-activity curve by monitoring continuously drawn arterial blood with an external detector: errors and corrections.

Accurate description of the arterial time-activity curve (ATAC) is of paramount importance in quantitative determination of the regional cerebral blood flow (rCBF) using positron tomography following bolus i.v. injection of 0-15 labeled water. Frequent manual sampling from an arterial catheter does not permit sampling in less than 5-sec intervals and runs the risk of missing the arrival time or the peak count. A continuous ATAC monitoring system has been developed. This system consists of a single bismuth germinate detector in a lead shield and a constant-flow aspirator. The arterial blood was drawn continuously from a catheter within the brachial artery into an extended tube and its activity was monitored by the detector as the detector time-activity curve (DTAC). Comparison with the manual sampling from the contralateral brachial artery in the same run revealed that the DTAC differed from the manual sampling not only in delayed arrival but also in the shape of the curve, which was dispersed because of viscosity and the width of the detector field of view. However, deconvolution of DTAC using the experimentally obtained system step response provided an accurate arterial time course, which successfully filled in the gaps of the manual sampling. Moreover, water and blood showed different dispersion in the step response, suggesting that the system function should be determined using blood or a fluid of similar hydrodynamic nature.