Dynamic Positron Emission Tomography Scans Research Articles

Performance and Sensitivity of [99mTc]Tc-sestamibi Compared with Positron Emission Tomography Radiotracers to Measure P-glycoprotein Function in the Kidneys and Liver.

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 [99mTc]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 [11C]N-desmethyl-loperamide, (R)-[11C]verapamil, or [11C]metoclopramide or consecutive static SPECT scans after intravenous injection of [99mTc]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 (CLurine,kidney) was significantly reduced (-83%) in Abcb1a/b(-/-) mice only for [99mTc]Tc-sestamibi. Biliary clearance of radioactivity (CLbile,liver) was significantly reduced in Abcb1a/b(-/-) mice for [11C]N-desmethyl-loperamide (-47%), [11C]metoclopramide (-25%), and [99mTc]Tc-sestamibi (-79%). However, in Abcb1a/b(+/-) mice, CLbile,liver was significantly reduced (-47%) only for [99mTc]Tc-sestamibi. Among the tested radiotracers, [99mTc]Tc-sestamibi performed best in measuring the P-gp function in the kidneys and liver. Owing to its widespread clinical availability, [99mTc]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.

Kinetic modeling and parametric imaging of 18 F-PSMA-11: An evaluation based on total-body dynamic positron emission tomography scans.

The prostate-specific membrane antigen (PSMA) targeted positron-emitting tomography (PET) tracers are increasingly used in clinical practice, with novel tracers constantly being developed. Recently, 18 F-PSMA-11 has been gaining growing interest for several merits; however, direct in vivo visualization of its kinetic features in humans remains lacking. To visualize the kinetic features of 18 F-PSMA-11 in healthy subjects and patients with prostate cancer derived from the total-body dynamic PET scans. A total of 8 healthy volunteers (7 males; 1 female) and 3 patients with prostate cancer underwent total-body PET/CT imaging at 1 and 2h post injection (p.i.) of 18 F-PSMA-11, of which 7 healthy subjects and 3 patients underwent total-body dynamic PET scans lasting 30min. Reversible two-tissue compartments (2TC) and Patlak models were fitted based on the voxel-based time activity curves (TACs), with the parametric images generated subsequently. Additionally, semi-automated segmentation of multiple organs was performed in the dynamic images to measure the SUVmean at different time points and in the parametric images to estimate the mean value of the kinetic parameters of these organs. 18 F-PSMA-11 showed quick accumulation within prostate cancer, as early as 45s after tracer injection. It was rapidly cleared from blood circulation and predominantly excreted through the urinary system. High and rapid radiotracer accumulation was observed in the liver, spleen, lacrimal glands, and salivary glands, whereas gradual accumulation was observed in the skeleton. Prostate cancer tissue is visualized in all parametric images, and best seen in DV and Patlak Ki images. Patlak Ki showed a good correlation with 2TC Ki values (r=0.858, p<0.05) but less noise than 2TC images. A scanning time point of 30-35min p.i. was then suggested for satisfactory tumor to background ratio. Prostate cancer tissue is visible in most parametric images, and is better shown by Patlak Ki and 2TC DV images. Patlak Ki is consistent with, and thus is preferred over, 2TC Ki images for substantially quicker calculation. Based on the dynamic imaging analysis, a shorter uptake time (30-35min) might be preferred for a better balance of tumor to background ratio.

Abstract 14190: Simultaneous Analysis of Myocardial Flow Reserve and Intra-Ventricular 4D Flow Using Hybrid 13 N-ammonia Positron Emission Tomography/Magnetic Resonance Imaging in Patients With Coronary Artery Disease

Introduction: Intra-left ventricular (LV) blood flow dynamics is closely related to wall kinetics and myocardial perfusion. 4D flow magnetic resonance imaging (MR) has been developed to simulate and quantify intra-LV blood flow. We aimed to evaluate the usefulness of simultaneous analysis of myocardial flow reserve (MFR) and intra-LV 4D flow measured by hybrid 13 N-ammonia positron emission tomography (PET)/MR in patients with coronary artery disease (CAD). Methods: Forty patients (mean 65±18 years, male 32) with CAD who underwent pharmacological stress PET/MR were enrolled. MFR was calculated from a series of dynamic rest-stress PET scans. Simultaneously, 4D flow MR acquisition was performed during the stress PET scan. The intra-LV 4D flow was visually assessed, where the smooth flow was defined as normal pattern, and random, or reverse flow was defined as abnormal (Figure A). The velocity of LV inflow and outflow were measured. Results: A normal flow pattern was found in 22 patients, while abnormal pattern was found in 18. MFR showed a significant correlation with the velocity of LV inflow and outflow (inflow: R = 0.552, P &lt; 0.001; outflow: R = 0.563, P &lt; 0.001). MFR was significantly lower in the abnormal flow compared to the normal flow (1.484 ± 0.559 vs. 1.931 ± 0.775, P = 0.041, Figure B). Additionally, when analyzing MFR in coronary artery territories, MFR in the left anterior descending artery was significantly lower in the abnormal flow compared to the normal flow (1.405 ± 0.526 vs. 1.881 ± 0.791, P = 0.029, Figure C). Conclusion: Simultaneous analysis of MFR and intra-LV 4D flow has a potential to serve as a novel indicator for assessing the severity of ischemia in patients with CAD.

3D-printed dual holder system for simultaneous rat PET scanning: design and influence on quantification

BackgroundThe low throughout of small animal positron emission tomography (PET) images acquisitions represents a substantial limitation. The aims of this study were (i) to design a low-cost support for simultaneous dynamic PET scanning of two lying rats and (ii) to study its impact on brain image quantification.ResultsAccuracy of concentration measurement was 5.5% for one phantom in the field of view, and 5.7% for two phantoms measured simultaneously. Ratio concentration between phantoms showed an error of 6.7% ± 5.1% for Solo upper position, 6.7% ± 3.7% for Solo lower position, 5.9% ± 4.3% for Duo upper position, and 7.4% ± 6% for Duo lower position 6.7% for separated measures, and 6.6% for simultaneous measures.In vivo distribution profiles showed no difference between solo and duo uptakes. Region of Interest quantification in the whole brain showed 4.4% variability solo and 3.5% duo. The quantified test–retest bias was 8% in solo and 5% in duo, and the Intraclass Correlation Coefficient was comparable in solo and duo (0.969 vs. 0.966).ConclusionsOur results showed that simultaneous scans of two rats in INVEON do not affect quantification. The dual support system will allow us to reduce protocol costs and duration.

Feasibility of Renal Blood Flow Measurement Using 64Cu-ATSM PET/MRI: A Quantitative PET and MRI Study.

This study aimed to evaluate the renal blood flow (RBF) in patients with chronic kidney disease (CKD) using 64Cu(II)-diacetyl-bis(4-methylthiosemicarbazonate) (64Cu-ATSM) for positron emission tomography (PET)/magnetic resonance imaging (MRI). We included five healthy controls (HCs) and ten patients with CKD. The estimated glomerular filtration rate (eGFR) was calculated from the serum creatinine (cr) and cystatin C (cys) levels. The estimated RBF (eRBF) was calculated using the eGFR, hematocrit, and filtration fraction. A single dose of 64Cu-ATSM (300-400 MBq) was administered for RBF evaluation, and a 40 min dynamic PET scan was performed with simultaneous arterial spin labeling (ASL) imaging. PET-RBF images were obtained from the dynamic PET images at 3 min after injection using the image-derived input function method. The mean eRBF values calculated from various eGFR values differed significantly between the patients and HCs; both groups also differed significantly in terms of the RBF values (mL/min/100 g) measured using PET (151 ± 20 vs. 124 ± 22, p < 0.05) and ASL-MRI (172 ± 38 vs. 125 ± 30, p < 0.001). The ASL-MRI-RBF was positively correlated with the eRBFcr-cys (r = 0.858, p < 0.001). The PET-RBF was positively correlated with the eRBFcr-cys (r = 0.893, p < 0.001). The ASL-RBF was positively correlated with the PET-RBF (r = 0.849, p < 0.001). 64Cu-ATSM PET/MRI demonstrated the reliability of PET-RBF and ASL-RBF by comparing them with eRBF. This is the first study to demonstrate that 64Cu-ATSM-PET is useful for assessing the RBF and is well correlated with ASL-MRI.

Feasibility Study to Assess Canagliflozin Distribution and Sodium-Glucose Co-Transporter 2 Occupancy Using [18 F]Canagliflozin in Patients with Type 2 Diabetes.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors, including canagliflozin, reduce the risk of cardiovascular and kidney outcomes in patients with and without type 2 diabetes, albeit with a large interindividual variation. The underlying mechanisms for this variation in response might be attributed to differences in SGLT2 occupancy, resulting from individual variation in plasma and tissue drug exposure and receptor availability. We performed a feasibility study for the use of [18 F]canagliflozin positron emission tomography (PET) imaging to determine the association between clinical canagliflozin doses and SGLT2 occupancy in patients with type 2 diabetes. We obtained two 90-minute dynamic PET scans with diagnostic intravenous [18 F]canagliflozin administration and a full kinetic analysis in 7 patients with type 2 diabetes. Patients received 50, 100, or 300 mg oral canagliflozin (n = 2:4:1) 2.5 hours before the second scan. Canagliflozin pharmacokinetics and urinary glucose excretion were measured. The apparent SGLT2 occupancy was derived from the difference between the apparent volume of distribution of [18 F]canagliflozin in the baseline and post-drug PET scans. Individual canagliflozin area under the curve from oral dosing until 24-hours (AUCP0-24h ) varied largely (range 1,715-25,747 μg/L*hour, mean 10,580 μg/L*hour) and increased dose dependently with mean values of 4,543, 6,525, and 20,012 μg/L*hour for 50, 100, and 300 mg, respectively (P = 0.046). SGLT2 occupancy ranged between 65% and 87%, but did not correlate with canagliflozin dose, plasma exposure, or urinary glucose excretion. We report the feasibility of [18 F]canagliflozin PET imaging to determine canagliflozin kidney disposition and SGLT2 occupancy. This suggests the potential of [18 F]canagliflozin as a tool to visualize and quantify clinically SGLT2 tissue binding.

Distribution of [11C]-JNJ-42491293 in the marmoset brain: a positron emission tomography study.

JNJ-42491293 is a metabotropic glutamate 2 (mGlu2) positive allosteric modulator (PAM) that was radiolabelled with [11C]- to serve as a positron emission tomography (PET) ligand. Indeed, in vitro, the molecule displays high selectivity at mGlu2 receptors. However, PET experiments performed in rats, macaques and humans, have suggested that [11C]-JNJ-42491293 could interact with an unidentified, non-mGlu2 receptor binding site. The brain distribution of [11C]-JNJ-42491293 has not been determined in the brain of the common marmoset, a small non-human primate increasingly used in neuroscience research. Here, we investigated the distribution of [11C]-JNJ-42491293 in the marmoset brain. Three marmosets underwent brain magnetic resonance imaging (MRI) and 90-min dynamic PET scans with [11C]-JNJ-42491293 in combination with vehicle or the mGlu2 PAM AZD8529 (0.1, 1 and 10mg/kg). In the scans in which [11C]-JNJ-42491293 was co-administered with vehicle, the brain areas with the highest standardised uptake values (SUVs) were the midbrain, cerebellum and thalamus, while the lowest SUVs were found in the pons. The addition of AZD8529 (0.1, 1 and 10mg/kg) to [11C]-JNJ-42491293 did not modify the SUVs obtained with [11C]-JNJ-42491293 alone, and ex vivo blocking autoradiography with PAM AZD8529 (10, 100, 300µM) on marmoset brain sections showed increased signals in the blocking conditions compared to vehicle, suggesting that no competition occurred between the 2 ligands. The results we obtained here do not suggest that [11C]-JNJ-42491293 interacts selectively, or even at all, with mGlu2 receptors in the marmoset, in agreement with findings previously reported in macaque and human.

Image-derived input functions from dynamic 15O–water PET scans using penalised reconstruction

BackgroundQuantitative positron emission tomography (PET) scans of the brain typically require arterial blood sampling but this is complicated and logistically challenging. One solution to remove the need for arterial blood sampling is the use of image-derived input functions (IDIFs). Obtaining accurate IDIFs, however, has proved to be challenging, mainly due to the limited resolution of PET. Here, we employ penalised reconstruction alongside iterative thresholding methods and simple partial volume correction methods to produce IDIFs from a single PET scan, and subsequently, compare these to blood-sampled input curves (BSIFs) as ground truth. Retrospectively we used data from sixteen subjects with two dynamic 15O-labelled water PET scans and continuous arterial blood sampling: one baseline scan and another post-administration of acetazolamide.ResultsIDIFs and BSIFs agreed well in terms of the area under the curve of input curves when comparing peaks, tails and peak-to-tail ratios with R2 values of 0.95, 0.70 and 0.76, respectively. Grey matter cerebral blood flow (CBF) values showed good agreement with an average difference between the BSIF and IDIF CBF values of 2% ± and a coefficient of variation (CoV) of 7.3%.ConclusionOur results show promising results that a robust IDIF can be produced for dynamic 15O–water PET scans using only the dynamic PET scan images with no need for a corresponding MRI or complex analytical techniques and thereby making routine clinical use of quantitative CBF measurements with 15O–water feasible.

Preclinical evaluation of a brain penetrant PARP PET imaging probe in rat glioblastoma and nonhuman primates.

Currently, there are multiple active clinical trials involving poly(ADP-ribose) polymerase (PARP) inhibitors in the treatment of glioblastoma. The noninvasive quantification of baseline PARP expression using positron emission tomography (PET) may provide prognostic information and lead to more precise treatment. Due to the lack of brain-penetrant PARP imaging agents, the reliable and accurate in vivo quantification of PARP in the brain remains elusive. Herein, we report the synthesis of a brain-penetrant PARP PET tracer, (R)-2-(2-methyl-1-(methyl-11C)pyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide ([11C]PyBic), and its preclinical evaluations in a syngeneic RG2 rat glioblastoma model and healthy nonhuman primates. We synthesized [11C]PyBic using veliparib as the labeling precursor, performed dynamic PET scans on RG2 tumor-bearing rats and calculated the distribution volume ratio (DVR) using simplified reference region method 2 (SRTM2) with the contralateral nontumor brain region as the reference region. We performed biodistribution studies, western blot, and immunostaining studies to validate the in vivo PET quantification results. We characterized the brain kinetics and binding specificity of [11C]PyBic in nonhuman primates on FOCUS220 scanner and calculated the volume of distribution (VT), nondisplaceable volume of distribution (VND), and nondisplaceable binding potential (BPND) in selected brain regions. [11C]PyBic was synthesized efficiently in one step, with greater than 97% radiochemical and chemical purity and molar activity of 148 ± 85MBq/nmol (n = 6). [11C]PyBic demonstrated PARP-specific binding in RG2 tumors, with 74% of tracer binding in tumors blocked by preinjected veliparib (i.v., 5mg/kg). The in vivo PET imaging results were corroborated by ex vivo biodistribution, PARP1 immunohistochemistry and immunoblotting data. Furthermore, brain penetration of [11C]PyBic was confirmed by quantitative monkey brain PET, which showed high specific uptake (BPND > 3) and low nonspecific uptake (VND < 3mL/cm3) in the monkey brain. [11C]PyBic is the first brain-penetrant PARP PET tracer validated in a rat glioblastoma model and healthy nonhuman primates. The brain kinetics of [11C]PyBic are suitable for noninvasive quantification of available PARP binding in the brain, which posits [11C]PyBic to have broad applications in oncology and neuroimaging.

Effect of budesonide on pulmonary activity of multidrug resistance-associated protein 1 assessed with PET imaging in rats

Multidrug resistance-associated protein 1 (MRP1/ABCC1) is a highly abundant efflux transporter in the lungs, which protects cells from toxins and oxidative stress and has been implicated in the pathophysiology of chronic obstructive pulmonary disease and cystic fibrosis. There is evidence from in vitro studies that the inhaled glucocorticoid budesonide can inhibit MRP1 activity. We used positron emission tomography (PET) imaging with 6-bromo-7-[11C]methylpurine ([11C]BMP), which is transformed in vivo into a radiolabeled MRP1 substrate, to assess whether intratracheally (i.t.) aerosolized budesonide affects pulmonary MRP1 activity in rats. Three groups of rats (n = 5–6 each) underwent dynamic PET scans of the lungs after i.t. aerosolization of either [11C]BMP alone, or [11C]BMP mixed with either budesonide (0.04 mg, corresponding to the maximum soluble dose) or the model MRP1 inhibitor MK571 (2 mg). From PET-measured radioactivity concentration-time curves, the rate constant describing radioactivity elimination from the right lung (kE,lung) and the area under the curve (AUClung) were calculated from 0 to 5 min after start of the PET scan as measures of pulmonary MRP1 activity. Co-administration of MK571 resulted in a pronounced decrease in kE,lung (25-fold, p < 0.0001) and an increase in AUClung (5.3-fold, p < 0.0001) when compared with vehicle-treated animals. In contrast, in budesonide-treated animals kE,lung and AUClung were not significantly different from the vehicle group. Our results show that i.t. aerosolized budesonide at an approximately 5 times higher dose than the maximum clinical dose leads to no change in pulmonary MRP1 activity, suggesting a lack of an effect of inhaled budesonide treatment on the MRP1-mediated cellular detoxifying capacity of the lungs. However, the strong effect observed for MK571 raises the possibility for the occurrence of transporter-mediated drug-drug interactions at the pulmonary epithelium with inhaled medicines.

Influence of P-glycoprotein on pulmonary disposition of the model substrate [11C]metoclopramide assessed by PET imaging in rats

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 [11C]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)-[11C]verapamil and [11C]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 [11C]metoclopramide. Lung exposure to [11C]metoclopramide was expressed as the area under the right lung concentration-time curve (AUClung). AUClung 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)-[11C]verapamil and [11C]N-desmethyl-loperamide, which showed decreased exposure in the rat lung in absence of P-gp activity. Our results suggest that transepithelial transfer of [11C]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 [11C]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.

Input function and modeling for determining bone metabolic flux using [18 F] sodium fluoride PET imaging: A step-by-step guide.

Studies of skeletal metabolism using measurements of bone metabolic flux (Ki ) obtained with [18 F] sodium fluoride ([18 F]NaF) positron emission tomography (PET) scans have been used in clinical research for the last 30 years. The technique has proven useful as an imaging biomarker in trials of novel drug treatments for osteoporosis and investigating other metabolic bone diseases, including chronic kidney disease mineral and bone disorder. It has also been shown to be valuable in metastatic bone disease in breast cancer patients and may have potential in other cancer types, such as prostate cancer, to assess early bone fracture risk. However, these studies have usually required a 60-min dynamic PET scan and measurement of the arterial input function (AIF), making them difficult to translate into the clinic for diagnostic purposes. We have previously proposed a simplified method that estimates the Ki value at an imaging site from a short (4-min) static scan and venous blood samples. A key advantage of this method is that, by acquiring a series of static scans, values of Ki can be quickly measured at multiple sites using a single injection of the tracer. To date, the widespread use of [18 F]NaF PET has been limited by the need to measure the AIF required for the mathematical modeling of tracer kinetics to derive Ki and other kinetic parameters. In this report, we review different methods of measuring the AIF, including direct arterial sampling, the use of a semi-population input function (SP-AIF), and image-derived input function, the latter two requiring only two or three venous blood samples obtained between 30 and 60min after injection. We provide an SP-AIF model and a spreadsheet for calculating Ki values using the static scan method that others can use to study bone metabolism in metabolic and metastatic bone diseases without requiring invasive arterial blood sampling. The method shortens scan times, simplifies procedures, and reduces the cost of multicenter trials without losing accuracy or precision.

Tau and amyloid PET imaging with 18F‐PI‐2620 and 18F‐Florbetaben in patients with early‐onset dementia and healthy controls

AbstractBackgroundAbnormal deposits of tau protein and beta‐amyloid are the two fundamental pathological features of Alzheimer's disease (AD). The research framework for AD diagnosis proposes categorizing subjects based on biomarker evidence of pathology using the ATN classification system (amyloid, tau, neurodegeneration). In‐vivo detection of amyloid pathology using positron emission tomography (PET) is well established and new generation tau PET tracers like 18F‐PI‐2620 have shown a high binding affinity for aggregated tau without significant off‐target binding. The purpose of this study is to describe the ability of 18F‐PI‐2620 to detect tau pathology in patients with early‐onset dementia (EOD) with proven amyloid pathology.MethodTen patients with EOD and positive 18F‐Florbetaben amyloid PET (age range 54‐64y, 8 with suspected early‐onset AD (EOAD) and 2 with logopenic variant primary progressive aphasia (lvPPA)), along with 14 healthy controls (HC) (age range 54‐76y) underwent dynamic PET scans for 75 minutes after injection of 18F‐PI‐2620 to examine the presence of tau‐pathology in cortical and deep brain regions. Specific binding ratios were derived from averaged PET images from 45‐75 min post‐injection.ResultIn 9 out of 10 EOD patients, 18F‐PI‐2620 uptake was robust and extensive predominantly in cortical regions with relative sparing of deep brain regions. In the remaining EOD case, binding was low but with the same distribution pattern described for other EOD patients. In one HC, significant, specific uptake was observed predominantly in deep brain regions. 18F‐PI‐2620 administration was safe and well‐tolerated.ConclusionOur preliminary results suggest an excellent performance of the tracer 18F‐PI‐2620 to detect tau deposits in EOAD and lvPPA. Tau PET imaging with 18F‐PI‐2620, in conjunction with 18F‐Florbetaben amyloid PET, distinctly discriminates between early‐onset dementias due to AD pathology from HC. These results also support the usefulness of 18F‐PI‐2620 for visualizing tau aggregation in EOD. Finally, 18F‐Florbetaben and 18F‐PI‐2620 appear to be reliable tools for establishing the ATN biomarker status in EOD patients. Nevertheless, further studies are needed to confirm these preliminary results.

Tau PET imaging with 18F‐PI‐2620 in patients with corticobasal syndrome: a case series

AbstractBackgroundCorticobasal syndrome (CBS) is the clinical phenotype originally described for corticobasal degeneration (CBD), a rare sporadic neurodegenerative 4‐repeat tauopathy, clinically characterized by the presence of asymmetric parkinsonism, apraxia, cortical sensory deficits, dystonia, myoclonus, and cognitive dysfunction. However, patients with CBS can have neurodegenerative pathology other than CBD, like progressive supranuclear palsy (PSP), Alzheimer's Disease (AD), Vascular Dementia, and Lewy body dementia. Selective tau tracers have made it possible to detect the presence of abnormal tau deposits in vivo. 18F‐PI‐2620 is a tau‐specific positron emission tomography (PET) tracer with a high binding affinity for aggregated tau. This study aims to investigate the potential role of 18F‐PI‐2620 as a biomarker in patients with CBS.MethodFour participants with clinical features consistent with probable CBS according to the 2013 Armstrong diagnostic criteria underwent dynamic PET scans for 75 min after injection of 18F‐PI‐2620. Specific binding ratios were derived from averaged PET images from 45‐75 min post‐injection.ResultFirst two patients had robust increases in 18F‐PI‐2620 uptake in temporal, parietal, and occipital cortical regions with relative sparing of globus pallidus and putamen. In the third patient, 18F‐PI‐2620 uptake was observed in the globus pallidus and putamen with relative sparing of cortical regions. The fourth patient had low 18F‐PI‐2620 uptake localized in the globus pallidus, temporal, and parietal regions.ConclusionIn the first two patients, 18F‐PI‐2620 binding distribution resembles what was described for Alzheimer's disease. In the third patient, 18F‐PI‐2620 uptake pattern suggests PSP. In this particular case, we hypothesize the definitive diagnosis is PSP‐CBS, a rare clinical presentation of PSP with CBS features. Finally, the fourth patient had low 18F‐PI‐2620 uptake but in areas clearly related to AD, PSP, and probably CBD. Our findings support CBS's heterogeneous pathological basis and suggest that 18F‐PI‐2620 could represent a valuable tool in the assessment of CBS, establishing an underlying tauopathy in most cases. However, we suspect 18F‐PI‐2620 in CBS is insufficient to distinguish, in some cases, AD pathology from other tauopathies. Therefore, the use of additional biomarkers to establish the presence of amyloid pathology should be considered. Further studies are needed to confirm these preliminary results.

Development and evaluation of an 18F-labeled nanobody to target SARS-CoV-2's spike protein

COVID-19, caused by the SARS-CoV-2 virus, has become a global pandemic that is still present after more than two years. COVID-19 is mainly known as a respiratory disease that can cause long-term consequences referred to as long COVID. Molecular imaging of SARS-CoV-2 in COVID-19 patients would be a powerful tool for studying the pathological mechanisms and viral load in different organs, providing insights into the disease and the origin of long-term consequences and assessing the effectiveness of potential COVID-19 treatments. Current diagnostic methods used in the clinic do not allow direct imaging of SARS-CoV-2. In this work, a nanobody (NB) – a small, engineered protein derived from alpacas – and an Fc-fused NB which selectively target the SARS-CoV-2 Spike protein were developed as imaging agents for positron emission tomography (PET). We used the tetrazine ligation to 18F-label the NB under mild conditions once the NBs were successfully modified with trans-cyclooctenes (TCOs). We confirmed binding to the Spike protein by SDS-PAGE. Dynamic PET scans in rats showed excretion through the liver for both constructs. Future work will evaluate in vivo binding to the Spike protein with our radioligands.

Intramuscular [18F]F-FDG Administration for Successful PET Imaging of Golden Hamsters in a Maximum Containment Laboratory Setting.

Positron emission tomography (PET) is becoming an important tool for the investigation of emerging infectious diseases in animal models. Usually, PET imaging is performed after intravenous (IV) radiotracer administration. However, IV injections are difficult to perform in some small animals, such as golden hamsters. This challenge is particularly evident in longitudinal imaging studies, and even more so in maximum containment settings used to study high-consequence pathogens. We propose the use of intramuscular (IM) administration of 2-deoxy-2[18F]fluoro-D-glucose ([18F]F-FDG) for PET imaging of hamsters in a biosafety level 4 (BSL-4) laboratory setting. After [18F]F-FDG administration via IM or IV (through surgically implanted vascular access ports), eight hamsters underwent static or dynamic PET scans. Time-activity curves (TACs) and standardized uptake values (SUVs) in major regions of interest (ROIs) were used to compare the two injection routes. Immediately after injection, TACs differed between the two routes. At 60 min post-injection, [18F]F-FDG activity for both routes reached a plateau in most ROIs except the brain, with higher accumulation in the liver, lungs, brain, and nasal cavities observed in the IM group. IM delivery of [18F]F-FDG is an easy, safe, and reliable alternative for longitudinal PET imaging of hamsters in a BSL-4 laboratory setting.

Development of a Neurotensin-Derived 68Ga-Labeled PET Ligand with High In Vivo Stability for Imaging of NTS1 Receptor-Expressing Tumors.

Simple SummaryCancer diagnostics based on molecular imaging techniques such as positron emission tomography (PET) requires radiolabeled tracers, which are taken up by tumors. As the neurotensin receptor type 1 (NTS1R) is present in certain malignant tumors, radiolabeled NTS1R ligands can serve as molecular tools for tumor imaging. A straightforward approach for developing NTS1R PET ligands would be the preparation of fluorine-18 or gallium-68 labeled analogs of the peptide neurotensin. However, as neurotensin derivatives are prone to enzymatic cleavage, structural modifications are needed to prevent peptide degradation while retaining NTS1R affinity. Applying a new strategy for peptide stabilization, it is possible to develop a peptidic gallium-68 labeled NTS1R PET ligand with high in vivo stability and high NTS1R affinity. Investigations of the PET ligand in mice with subcutaneous NTS1R-positive tumors revealed the NTS1R-mediated visualization of the tumor. Future developments, such as NTS1R PET ligands with improved biodistribution, will benefit from these results.Overexpression of the neurotensin receptor type 1 (NTS1R), a peptide receptor located at the plasma membrane, has been reported for a variety of malignant tumors. Thus, targeting the NTS1R with 18F- or 68Ga-labeled ligands is considered a straightforward approach towards in vivo imaging of NTS1R-expressing tumors via positron emission tomography (PET). The development of suitable peptidic NTS1R PET ligands derived from neurotensin is challenging due to proteolytic degradation. In this study, we prepared a series of NTS1R PET ligands based on the C-terminal fragment of neurotensin (NT(8–13), Arg8-Arg9-Pro10-Tyr11-Ile12-Leu13) by attachment of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) via an Nω-carbamoylated arginine side chain. Insertion of Ga3+ in the DOTA chelator gave potential PET ligands that were evaluated concerning NTS1R affinity (range of Ki values: 1.2–21 nM) and plasma stability. Four candidates were labeled with 68Ga3+ and used for biodistribution studies in HT-29 tumor-bearing mice. [68Ga]UR-LS130 ([68Ga]56), containing an N-terminal methyl group and a β,β-dimethylated tyrosine instead of Tyr11, showed the highest in vivo stability and afforded a tumor-to-muscle ratio of 16 at 45 min p.i. Likewise, dynamic PET scans enabled a clear tumor visualization. The accumulation of [68Ga]56 in the tumor was NTS1R-mediated, as proven by blocking studies.

Patlak plot based on the first 30 minutes post-injection dynamic 18F-florbetaben positron emission tomography scan separates amyloid-β positive from negative studies.

This work aims to search for the shortest duration of an early 18F-florbetaben positron emission tomography (PET) dynamic acquisition to obtain reliable information on the brain amyloid-β (Aβ) deposition and perfusion. 25 patients that underwent an early 18F-florbetaben PET dynamic acquisition starting immediately post-injection (maximum of 60 min duration) were retrospectively included. Reference region-based Patlak plot [Formula: see text] (transference rate to the irreversible compartment) and [Formula: see text] (distribution volume) were computed. Shorter early dynamic acquisitions were simulated to a minimum of 15 min duration. Three nuclear medicine physicians evaluated qualitatively the [Formula: see text] parametric images obtained in comparison with those obtained from the standard clinical protocol defined by a late acquisition of 20 min duration starting 90 min post-injection. All the [Formula: see text] parametric images obtained with at least an early 30-min dynamic acquisitions were suitable for visual classification. Shorter early acquisitions originated images with too much noise, making qualitative assessment difficult. Aβ deposition visual classification based on the [Formula: see text] images were highly concordant with the evaluation of standard late acquisitions (readers consensus agreement of 92%). [Formula: see text] images obtained from the different early dynamic acquisition's duration were visually indistinguishable from each other (voxelwise r ≥ 0.98). Patlak plot method applied to early 30-min 18F-florbetaben PET dynamic acquisition may be an alternative to the dual acquisition protocol sometimes used in clinics. This improves patients' comfort, service logistics and reduces radiation exposure. This work shows, for the first time, that early (0-30 min post-injection) 18F-florbetaben dynamic PET scans with reference region-based Patlak plot method could replace the dual acquisition protocol and the 90-110 min standard acquisition.

First-in-human use of 11C-CPPC with positron emission tomography for imaging the macrophage colony-stimulating factor 1 receptor

PurposeStudy of the contribution of microglia to onset and course of several neuropsychiatric conditions is challenged by the fact that these resident immune cells often take on different phenotypes and functions outside the living brain. Imaging microglia with radiotracers developed for use with positron emission tomography (PET) allows researchers to study these cells in their native tissue microenvironment. However, many relevant microglial imaging targets such as the 18 kDa translocator protein are also expressed on non-microglial cells, which can complicate the interpretation of PET findings. 11C-CPPC was developed to image the macrophage colony-stimulating factor 1 receptor, a target that is expressed largely by microglia relative to other cell types in the brain. Our prior work with 11C-CPPC demonstrated its high, specific uptake in brains of rodents and nonhuman primates with neuroinflammation, which supports the current first-in-human evaluation of its pharmacokinetic behavior in the brains of healthy individuals.MethodsEight healthy nonsmoker adults completed a 90-min dynamic PET scan that began with bolus injection of 11C-CPPC. Arterial blood sampling was collected in order to generate a metabolite-corrected arterial input function. Tissue time-activity curves (TACs) were generated using regions of interest identified from co-registered magnetic resonance imaging data. One- and two-tissue compartmental models (1TCM and 2TCM) as well as Logan graphical analysis were compared.ResultsCortical and subcortical tissue TACs peaked by 37.5 min post-injection of 11C-CPPC and then declined. The 1TCM was preferred. Total distribution volume (VT) values computed from 1TCM aligned well with those from Logan graphical analysis (t* = 30), with VT values relatively high in thalamus, striatum, and most cortical regions, and with relatively lower VT in hippocampus, total white matter, and cerebellar cortex.ConclusionOur results extend support for the use of 11C-CPPC with PET to study microglia in the human brain.

Comparison between a dual-time-window protocol and other simplified protocols for dynamic total-body 18F-FDG PET imaging

PurposeEfforts have been made both to avoid invasive blood sampling and to shorten the scan duration for dynamic positron emission tomography (PET) imaging. A total-body scanner, such as the uEXPLORER PET/CT, can relieve these challenges through the following features: First, the whole-body coverage allows for noninvasive input function from the aortic arteries; second, with a dramatic increase in sensitivity, image quality can still be maintained at a high level even with a shorter scan duration than usual. We implemented a dual-time-window (DTW) protocol for a dynamic total-body 18F-FDG PET scan to obtain multiple kinetic parameters. The DTW protocol was then compared to several other simplified quantification methods for total-body FDG imaging that were proposed for conventional setup.MethodsThe research included 28 patient scans performed on an uEXPLORER PET/CT. By discarding the corresponding data in the middle of the existing full 60-min dynamic scan, the DTW protocol was simulated. Nonlinear fitting was used to estimate the missing data in the interval. The full input function was obtained from 15 subjects using a hybrid approach with a population-based image-derived input function. Quantification was carried out in three areas: the cerebral cortex, muscle, and tumor lesion. Micro- and macro-kinetic parameters for different scan durations were estimated by assuming an irreversible two-tissue compartment model. The visual performance of parametric images and region of interest-based quantification in several parameters were evaluated. Furthermore, simplified quantification methods (DTW, Patlak, fractional uptake ratio [FUR], and standardized uptake value [SUV]) were compared for similarity to the reference net influx rate Ki.ResultsKi and K1 derived from the DTW protocol showed overall good consistency (P < 0.01) with the reference from the 60-min dynamic scan with 10-min early scan and 5-min late scan (Ki correlation: 0.971, 0.990, and 0.990; K1 correlation: 0.820, 0.940, and 0.975 in the cerebral cortex, muscle, and tumor lesion, respectively). Similar correlationss were found for other micro-parameters. The DTW protocol had the lowest bias relative to standard Ki than any of the quantification methods, followed by FUR and Patlak. SUV had the weakest correlation with Ki. The whole-body Ki and K1 images generated by the DTW protocol were consistent with the reference parametric images.ConclusionsUsing the DTW protocol, the dynamic total-body FDG scan time can be reduced to 15 min while obtaining accurate Ki and K1 quantification and acceptable visual performance in parametric images. However, the trade-off between quantification accuracy and protocol implementation feasibility must be considered in practice. We recommend that the DTW protocol be used when the clinical task requires reliable visual assessment or quantifying multiple micro-parameters; FUR with a hybrid input function may be a more feasible approach to quantifying regional metabolic rate with a known lesion position or organs of interest.