Evaluation of [11C]-DAA1106 for imaging and quantification of neuroinflammation in a rat model of herpes encephalitis

IntroductionMany neurological and psychiatric disorders are associated with neuroinflammation. Positron emission tomography (PET) with [¹¹C]-PK11195 can be used to study neuroinflammation in these disorders. However, [¹¹C]-PK11195 may not be sensitive enough to visualize mild neuroinflammation. As a potentially more sensitive PET tracer for neuroinflammation, [¹¹C]-N-(2,5-dimethoxybenzyl)-N-(4-fluoro-2-phenoxyphenyl)-acetamide (DAA1106) was evaluated in a rat model of herpes encephalitis.MethodsMale Wistar rats were intranasally inoculated with HSV-1 (HSE) or phosphate-buffered saline (control). At Day 6 or Day 7 after inoculation, small-animal [¹¹C]-DAA1106 PET scans were acquired, followed by ex vivo biodistribution. Arterial blood sampling was performed for quantification of uptake.ResultsIn HSE rats, a significantly higher ex vivo, but not in vivo, uptake of [¹¹C]-DAA1106 was found in almost all examined brain areas (24–71%, P<.05), when compared to control rats. Pretreatment with unlabeled PK11195 effectively reduced [¹¹C]-DAA1106 uptake in HSE rats (54–84%; P<.001). The plasma and brain time–activity curves showed rapid uptake of [¹¹C]-DAA1106 into tissue. The data showed a good fit to the Logan analysis but could not be fitted to a two-tissue compartment model.Conclusions[¹¹C]-DAA1106 showed a high and specific ex vivo uptake in the encephalitic rat brain. However, neuroinflammation could not be demonstrated in vivo by [¹¹C]-DAA1106 PET. Quantification of the uptake of [¹¹C]-DAA1106 using plasma sampling is not optimal, due to rapid tissue uptake, slow tissue clearance and low plasma activity.     

Human biodistribution and radiation dosimetry of 11C-(R)-PK11195, the prototypic PET ligand to image inflammation

Purpose  

The positron emission tomography (PET) radiotracer ¹¹C-(R)-PK11195 allows the in vivo imaging in humans of the translocator protein 18 kDa (TSPO), previously called peripheral benzodiazepine receptor (PBR), a marker of inflammation. Despite its widespread use, the radiation burden associated with ¹¹C-(R)-PK11195 in humans is not known. To examine this, we performed dynamic whole-body imaging with PET and ¹¹C-(R)-PK11195 in healthy humans.     

Radiosynthesis and ex vivo evaluation of (R)-(−)-2-chloro-N-[1-11C-propyl]n-propylnorapomorphine

IntroductionSeveral dopamine D₂ agonist radioligands have been used with positron emission tomography (PET), including [¹¹C-]-(?)-MNPA, [¹¹C-]-(?)-NPA and [¹¹C]-(+)-PHNO. These radioligands are considered particularly powerful for detection of endogenous dopamine release, but they either provide PET brain images with limited contrast or have affinity for both D₂ and D₃ receptors. We here present the carbon-11 radiolabeling and ex vivo evaluation of 2-Cl-(?)-NPA, a novel PET-tracer candidate with high in vitro D₂/D₃ selectivity.Methods2-Cl-[¹¹C]-(?)-NPA and [¹¹C]-(?)-NPA were synthesized by a two step N-acylation-reduction process using [¹¹C]-propionyl chloride. Awake rats were injected with either tracer, via the tail vein. The rats were decapitated at various times, the brains were removed and quickly dissected, and plasma metabolites were measured. Radioligand specificity, and P-glycoprotein involvement in brain uptake, was also assessed.Results2-Cl-[¹¹C]-(?)-NPA and [¹¹C]-(?)-NPA were produced in high specific activity and purity. 2-Cl-[¹¹C]-(?)-NPA accumulated slower in the striatum than [¹¹C]-(?)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[¹¹C]-(?)-NPA (standard uptake value 0.72±0.24) was approximately half that of [¹¹C]-(?)-NPA (standard uptake value 1.37±0.18). Nonspecific uptake was similar for the two compounds. 2-Cl-[¹¹C]-(?)-NPA was metabolized quickly, leaving only 17% of the parent compound in the plasma after 30 min. The specific binding of 2-Cl-[¹¹C]-(?)-NPA was completely blocked and inhibition of P-glycoprotein did not alter the brain uptake.ConclusionEx vivo experiments showed, despite a favorable D₂/D₃ selectivity, that 2-Cl-[¹¹C]-(?)-NPA is inferior to [¹¹C]-(?)-NPA as a PET tracer in rat, because of slower brain uptake and lower specific to nonspecific binding ratio.     

Microglial activation in perinatal rabbit brain induced by intrauterine inflammation: detection with 11C-(R)-PK11195 and small-animal PET.

Intrauterine infection can lead to a fetal inflammatory response syndrome that has been implicated as one of the causes of perinatal brain injury leading to periventricular leukomalacia (PVL) and cerebral palsy. The presence of activated microglial cells has been noted in autopsy specimens of patients with PVL and in models of neonatal hypoxia and ischemia. Activated microglial cells can cause oligodendrocyte damage and white matter injury by release of inflammatory cytokines and production of excitotoxic metabolites. We hypothesized that exposure to endotoxin in utero leads to microglial activation in the fetal brain that can be monitored in vivo by (11)C-(R)-PK11195 (1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide)--a positron-emitting ligand that binds peripheral benzodiazepine receptor sites in activated microglia--using small-animal PET. METHODS: Pregnant New Zealand White rabbits underwent laparotomy and were injected with 20 and 30 microg/kg of Escherichia coli lipopolysaccharide along the length of the uterus on day 28 of gestation. The pups were born spontaneously at term (31 d) and were scanned using small-animal PET after intravenous administration of (11)C-(R)-PK11195 and by MRI on postnatal day 1. The standard uptake values (SUVs) of the tracer were calculated for the whole brain at 10-min intervals for 60 min after tracer injection. The pups were euthanized after the scan, and brains were fixed, sectioned, and stained for microglial cells using biotinylated tomato lectin. RESULTS: There was increased brain retention of (11)C-(R)-PK11195--as determined by a significant difference in the slope of the SUV over time--in the endotoxin-treated pups when compared with that of age-matched controls. Immunohistochemical staining showed dose-dependent changes in activated microglia (increased number and morphologic changes) in the periventricular region and hippocampus of the brain of newborn rabbit pups exposed to endotoxin in utero. CONCLUSION: Intrauterine inflammation leads to activation of microglial cells that may be responsible for the development of brain injury and white matter damage in the perinatal period. PET with the tracer (11)C-(R)-PK11195 can be used as a noninvasive, sensitive tool for determining the presence and progress of neuroinflammation due to perinatal insults in newborns.     

Imaging of peripheral-type benzodiazepine receptor in tumor: in vitro binding and in vivo biodistribution of N-benzyl-N-[C]methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide

IntroductionThe aim of this study was to evaluate N-benzyl-N-[¹¹C]methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([¹¹C]DAC) as a novel peripheral-type benzodiazepine receptor (PBR) ligand for tumor imaging.Methods[¹¹C]DAC was synthesized by the reaction of a desmethyl precursor with [¹¹C]CH₃I. In vitro uptake of [¹¹C]DAC was examined in PBR-expressing C6 glioma and intact murine fibrosarcoma (NFSa) cells. In vivo distribution of [¹¹C]DAC was determined using NFSa-bearing mice and small-animal positron emission tomography (PET).Results[¹¹C]DAC showed specific binding to PBR in C6 glioma cells, a standard cell line with high PBR expression. Specific binding of [¹¹C]DAC was also confirmed in NFSa cells, a target tumor cell line in this study. Results of PET experiments using NFSa-bearing mice, showed that [¹¹C]DAC was taken up specifically into the tumor, and pretreatment with PK11195 abolished the uptake.Conclusions[¹¹C]DAC was taken up into PBR-expressing NFSa. [¹¹C]DAC is a promising PET ligand that can be used for imaging PBR in tumor-bearing mice.     

Whole-body distribution and metabolism of [N-methyl-11C](R)-1-(2-chlorophenyl)-N-(1-methylpropyl)-3-isoquinolinecarboxamide in humans; an imaging agent for in vivo assessment of peripheral benzodiazepine receptor activity with positron emission tomography

Purpose   ¹¹C-PK11195 is a radiopharmaceutical for in vivo assessment of peripheral benzodiazepine receptor (PBR) activity using PET. We sought to clarify the metabolic fate of ¹¹C-PK11195 in a test–retest setting using radio-HPLC in comparison with radio-TLC, and the whole-body distribution in humans. Materials and methods  In order to evaluate the reproducibility of radio-HPLC metabolite analyses, ten patients with Alzheimer’s disease (AD) underwent two successive ¹¹C-PK11195 examinations on separate days. For comparison of different analytical methods, plasma samples from seven patients were also analysed by radio-TLC. In addition, we evaluated the whole-body distribution of ¹¹C-PK11195 and its uptake in the brain. Results  The level of unmetabolized ¹¹C-PK11195 decreased slowly from 96.3 ± 1.6% (mean±SD) at 5 min to 62.7 ± 8.3% at 40 min after injection. Large individual variation was observed in the amount of plasma ¹¹C-PK11195 radiometabolites. The whole-body distribution of ¹¹C-PK11195 showed the highest radioactivity levels in urinary bladder, adrenal gland, liver, salivary glands, heart, kidneys, and vertebral column. In addition, the hip bone and breast bone were clearly visualized by PET. In patients with AD, ¹¹C-PK11195 uptake in the brain was the highest in the basal ganglia and thalamus, followed by the cortical grey matter regions and the cerebellum. Low ¹¹C-PK11195 uptake was observed in the white matter. Conclusion  Our results indicate that ¹¹C-PK11195 is eliminated both through the renal and hepatobiliary systems. Careful analysis of plasma metabolites is required to determine the accurate arterial input function for quantitative PET measurement.     

Preliminary feasibility study on differential diagnosis between radiation-induced cerebral necrosis and recurrent brain tumor by means of [<Superscript>18</Superscript>F]fluoro-borono-phenylalanine PET/CT

Objectives

A previous study reported that a differential diagnosis between glioblastoma progression and radiation necrosis by 4-borono-2-[¹⁸F]-fluoro-phenylalanine ([¹⁸F]FBPA) PET can be made based on lesion-to-normal ratio of [¹⁸F]FBPA accumulation. Two-dimensional data acquisition mode PET alone system, with in-plane resolution of 7.9 mm and axial resolution of 13.9 mm, was used. In the current study, we aimed to confirm the differential diagnostic capability of [¹⁸F]FBPA PET/CT with higher PET spatial resolution by three-dimensional visual inspection and by measuring mean standardized uptake value (SUVmean), maximum SUV (SUVmax), metabolic tumor volume (MTV), and total lesion (TL) [¹⁸F]FBPA uptake.

Methods

Twelve patients of glioma (9), malignant meningioma (1), hemangiopericytoma (1), and metastatic brain tumor (1) were enrolled. All had preceding radiotherapy. High-resolution three-dimensional data acquisition mode PET/CT with in-plane resolution of 4.07 mm and axial resolution of 5.41 mm was employed for imaging. Images were three-dimensionally analyzed using the PMOD software. SUVmean and SUVmax of lesion and normal brain were measured. Lesion MTV and TL FBPA uptake were calculated. The diagnostic accuracy of [¹⁸F]FBPA PET/CT in detecting recurrence (n?=?6) or necrosis (n?=?6) was verified by clinical follow-up.

Results

All parameters showed significantly higher values for tumor recurrence than for necrosis. SUVmean in recurrence was 2.95?±?0.84 vs 1.18?±?0.24 in necrosis (P?=?0.014); SUVmax in recurrence was 4.63?±?1.23 vs 1.93?±?0.44 in necrosis (P?=?0.014); MTV in recurrence was 44.92?±?28.93 mL vs 10.66?±?8.46 mL in necrosis (P?=?0.032); and mean TL FBPA uptake in recurrence was 121.01?±?50.48 g vs 12.36?±?9.70 g in necrosis (P?=?0.0029).

Conclusion

In this preliminary feasibility study, we confirmed the possibility of differentiating tumor recurrence from radiation necrosis in patients with irradiated brain tumors by [¹⁸F]FBPA PET/CT using indices of SUVmean, SUVmax, MTV, and TL ¹⁸FBPA uptake.

     

Comparison of L-type amino acid transporter 1 expression and L-[3-18F]-α-methyl tyrosine uptake in outcome of non-small cell lung cancer

Objectivel-Type amino acid transporter 1 (LAT1) has associated with tumor growth and poor outcome of patients with non-small cell lung cancer (NSCLC). l-[3-¹⁸F]-α-methyl tyrosine (¹⁸F-FAMT) is an amino acid tracer for positron emission tomography (PET) imaging, and ¹⁸F-FAMT uptake is mediated by LAT1. The purpose of this study is to compare the prognostic significance of ¹⁸F-FAMT uptake in the primary tumors with that of LAT1 expression in patients with NSCLC.MethodsFifty-nine patients with NSCLC were enrolled in this study. All patients underwent ¹⁸F-FAMT PET prior to resection of the tumor, and immunohistochemical staining of the resected tumors were performed to compare the ¹⁸F-FAMT uptake and LAT1 expression. Uptake of ¹⁸F-FAMT was evaluated using semiquantitative standardized uptake value (SUV_max), and the cutoff value was determined to discriminate patients with high SUV_max from those with low SUV_max. Expression of LAT1 was evaluated by the score of staining intensity through 1 to 4. SUV_max and LAT1 expression were compared according to the clinicopathological variables.ResultsThe best discriminative cutoff value of ¹⁸F-FAMT SUV_max within the primary tumors was 1.6. The high SUV_max (>1.6) in ¹⁸F-FAMT PET was significantly associated with male, and positive LAT1 expression was significantly associated with male and nonadenocarcinoma. In the univariate analysis, high SUV_max (>1.6) in ¹⁸F-FAMT PET and positive LAT1 expression were significant predictor of the poor outcome. Multivariate analysis confirmed that positive LAT1 expression was an independent and significant factor for predicting poor prognosis in NSCLC (P=.035).ConclusionLAT1 expression is a stronger prognostic factor than ¹⁸F-FAMT uptake in surgically resected NSCLC.     

Correlation of 4′-[methyl-<Superscript>11</Superscript>C]-thiothymidine uptake with Ki-67 immunohistochemistry and tumor grade in patients with newly diagnosed gliomas in comparison with <Superscript>11</Superscript>C-methionine uptake

Objective

A novel radiopharmaceutical, 4′-[methyl-¹¹C]thiothymidine (¹¹C-4DST), has been developed as an in vivo cell proliferation marker based on the DNA incorporation method. The purpose of this study was to evaluate ¹¹C-4DST uptake in patients with newly diagnosed glioma and to correlate the results with proliferative activity and tumor grade, in comparison with l-[methyl-¹¹C]-methionine (¹¹C-MET).

Methods

Investigations of ¹¹C-4DST and ¹¹C-MET PET/CT were performed retrospectively in 23 patients with newly diagnosed glioma. The maximum standardized uptake value (SUVmax) for tumor (T) and the mean SUV for normal contralateral hemisphere (N) were calculated, and the tumor-to-normal (T/N) ratio was determined. Metabolic tumor volume (MTV) was defined as the volume with a threshold of 40 % of the SUVmax. Proliferative activity as indicated by the Ki-67 index was estimated in tissue specimens.

Results

Of 23 gliomas examined, ¹¹C-4DST PET/CT and ¹¹C-MET PET/CT detected 20 and 22, respectively. Linear regression analysis between ¹¹C-4DST and ¹¹C-MET indicated a weak correlation for SUVmax (r = 0.54, P < 0.008), for T/N ratio (r = 0.56, P < 0.006), and for MTV (r = 0.60, P < 0.003). Linear regression analysis indicated a weak correlation between ¹¹C-4DST and Ki-67 index for SUVmax (r = 0.46, P < 0.03), for T/N ratio (r = 0.43, P < 0.05), and for MTV (r = 0.68, P < 0.001) and between ¹¹C-MET MTV and Ki-67 index (r = 0.43, P < 0.04). Using ¹¹C-4DST, there was a significant difference in SUVmax between grades II and IV (P < 0.03) and in MTV between grades II and IV (P < 0.009) and grades III and IV (P < 0.02). Using ¹¹C-MET, there was a significant difference in SUVmax (P < 0.009) and T/N ratio (P < 0.02) between grades II and IV and in MTV between grades II and IV (P < 0.03) and grades III and IV (P < 0.02).

Conclusion

¹¹C-4DST PET/CT is feasible for imaging of brain gliomas, as well as ¹¹C-MET PET/CT. Especially, it showed the highest correlation coefficient between ¹¹C-4DST MTV and Ki-67 index in newly diagnosed gliomas.

     

In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass

IntroductionThe positron emission tomography (PET) tracer 9-[¹⁸F]fluoroethyl-(+)-dihydrotetrabenazine ([¹⁸F]-FE-(+)-DTBZ) is a potential candidate for quantifying beta-cell mass in vivo. The purpose was to investigate in vitro and in vivo utility of this tracer for the assessment of beta-cell mass.MethodsThree pigs were intravenously administered [¹⁸F]-FE-(+)-DTBZ and examined by PET/computed tomography. Binding parameters were estimated by kinetic modeling. In vitro k_D and B_max were determined by saturation binding studies of endocrine and exocrine human tissue homogenates. In vitro pancreatic uptake was determined by tissue autoradiography with pancreases from patients with types 1 (T1DM) and 2 diabetes mellitus (T2DM) and healthy controls.Results[¹⁸F]-FE-(+)-DTBZ had a k_D of 3.5±1.0 nM, a B_max of 382±108 fmol/mg protein and a specificity of 89±1.8% in islet homogenates. The total exocrine uptake was lower and 65% was nondisplaceable. No uptake difference was observed in pancreatic tissue slices from patients with T1DM, T2DM or healthy controls. The in vivo porcine pancreatic uptake reached a peak of standardized uptake value (SUV) of 2.8 with a low distribution volume ratio in all animals. Moderate to high tracer uptake was identified in the bile system and in bone.Conclusions[¹⁸F]-FE-(+)-DTBZ binds to vesicular monoamine transporter 2 (VMAT2) with high specificity in pure islet tissue in vitro. However, there is high nondisplaceable binding to exocrine tissue. In addition, in vivo tracer metabolism and dehalogenation result in severe underestimation of porcine pancreatic VMAT2 expression and BCM. The results do not support [¹⁸F]-FE-(+)-DTBZ as a suitable tracer for in vivo beta-cell imaging.     

In vivo imaging and quantitative analysis of TSPO in rat peripheral tissues using small-animal PET with [18F]FEDAC

IntroductionThe translocator protein (18 kDa) (TSPO) is widely expressed in peripheral tissues, including the heart, lung, and kidney. Our laboratory developed N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[¹⁸F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide ([¹⁸F]FEDAC) as a TSPO positron emission tomography (PET) ligand. Here, using small-animal PET with [¹⁸F]FEDAC, we performed TSPO imaging and quantitative analysis of TSPO binding in rat peripheral tissues.MethodsThe in vivo distribution and kinetics of [¹⁸F]FEDAC were measured in rat peripheral tissues (heart, lung and kidney). Using the in vivo pseudo-equilibrium method, TSPO binding parameters [TSPO density (B_max), dissociation constant (K_D)] and receptor occupancy were estimated in these peripheral tissues.Results[¹⁸F]FEDAC was highly distributed in the lung, heart and kidney, and these TSPO-enriched tissues could be clearly visualized. The kinetics of this radioligand in these tissues was rapid, which is suitable for the determination of in vivo TSPO binding parameters and receptor occupancy. The B_max value of TSPO in the heart, lung, and kidney was 393, 141, and 158 pmol/ml, respectively. The K_D value of the radioligand in the heart, lung, and kidney was 119, 36 and 123 nM, respectively. By pretreatment with 5 mg/kg Ro 5-4864 (a TSPO ligand), about 90% of binding sites for TSPO in the heart and lung were occupied. In the kidney, the binding sites were completely occupied by 5 mg/kg Ro 5-4864.Conclusions[¹⁸F]FEDAC is a suitable PET ligand for TSPO imaging and quantitative analysis of TSPO binding in rat peripheral tissues. The utilization of [¹⁸F]FEDAC-PET and the pseudo-equilibrium method can contribute to the study of the TSPO function and evaluate the in vivo binding parameters and receptor occupancy of TSPO therapeutic compounds.     

Synthesis and evaluation of a C-6 alkylated pyrimidine derivative for the in vivo imaging of HSV1-TK gene expression

IntroductionWe report on the synthesis, radiolabeling, in vitro and in vivo characterization of N-Me-[¹⁸F]FHBT (6-(3-[¹⁸F]fluoro-2-(hydroxymethyl)propyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione), a C-6-substituted N-1-methylated pyrimidine derivative as a reporter probe for imaging herpes simplex virus type 1 thymidine kinase (HSV1-TK) expression.MethodsN-Me-[¹⁸F]FHBT was synthesized via a standard nucleophilic substitution reaction followed by acidic cleavage of the methoxytrityl protecting group. Cell uptake was studied in vitro with control HEK293 (human embryonic kidney cells) and HEK293 cells stably transfected with nonmutant HSV1-tk (HEK293TK+ cells). Positron emission tomography (PET) imaging and biodistribution studies of N-Me-[¹⁸F]FHBT or [¹⁸F]FHBG were performed in nude mice bearing xenografts of HEK293 control and TK+ cells.ResultsN-Me-[¹⁸F]FHBT was obtained in a two-step reaction in an overall maximal radiochemical yield (decay-corrected) of 5% and a radiochemical purity >96%. The tracer uptake in HSV1-TK containing HEK293TK+ cells was 14.5 times (at 30 min) and 55.4 times (at 240 min) higher than in control HEK293 cells. In mice, N-Me-[¹⁸F]FHBT and [¹⁸F]FHBG accumulated significantly and exhibited similar radioactivity levels in the HEK293TK+ xenografts; however, standardized uptake values ratios between HEK293TK+ and HEK293 control xenografts were higher for [¹⁸F]FHBG than for N-Me-[¹⁸F]FHBT. Both tracers showed high gall bladder and abdominal activity.ConclusionThe biological evaluations demonstrated the feasibility of using N-methylated C-6-substituted pyrimidine derivative N-Me-[¹⁸F]FHBT as a PET radiotracer for monitoring HSV1-TK expression in vivo.     

Evaluation of 68Ga-labeled tracers for PET imaging of myocardial perfusion in pigs

PurposeWe evaluated four potential gallium-68 (⁶⁸Ga)-labeled tracers for positron emission tomography (PET) imaging of myocardial perfusion in comparison with oxygen-15-labeled water ([¹⁵O]water) in healthy pigs. Four hexadentate salicylaldimine ligands derived from bis(3-aminopropyl)ethylenediamine (BAPEN) that showed promise in previous rat experiments were selected for this study.MethodsFollowing an evaluation of myocardial blood flow with [¹⁵O]water PET, the pigs (total n=14) underwent a dynamic 90-min PET study with one of four ⁶⁸Ga-labeled BAPEN derivatives (n=3–5 per tracer) either at rest or under adenosine stress. Serial arterial blood samples were collected during the imaging for the measurements of total radioactivity, radiometabolites, plasma protein binding and blood-to-plasma ratio for the ⁶⁸Ga chelates. Time–activity curves of the left ventricular blood pool and myocardium were derived from PET images, and metabolite-corrected arterial input function was used for kinetic modeling. Also, ex vivo biodistribution of ⁶⁸Ga radioactivity was analyzed.ResultsAll four ⁶⁸Ga tracers showed undesirably slow myocardial accumulation over time, but their in vivo stability, clearance from blood and the kinetics of the myocardium uptake varied. [⁶⁸Ga][Ga-(sal)₂BAPDMEN]¹⁺ showed the highest myocardial uptake in PET images and tissue samples (myocardium-to-blood ratio 7.63±1.89, myocardium-to-lung ratio 3.03±0.33 and myocardium-to-liver ratio 1.80±0.82). However, there was no correlation between the myocardial perfusion measured with [¹⁵O]water and the net uptake rates or K₁ values of the ⁶⁸Ga chelates.ConclusionOur results revealed that myocardial accumulation of the ⁶⁸Ga chelates proposed for myocardial perfusion imaging with PET was slow and not determined by myocardial perfusion in a large animal model. These findings suggest that the studied tracers are not suitable for clinical imaging of myocardial perfusion.     

Comparison of MR-based attenuation correction and CT-based attenuation correction of whole-body PET/MR imaging

Purpose

The objective of this study was to evaluate the performance of the built-in MR-based attenuation correction (MRAC) included in the combined whole-body Ingenuity TF PET/MR scanner and compare it to the performance of CT-based attenuation correction (CTAC) as the gold standard.

Methods

Included in the study were 26 patients who underwent clinical whole-body FDG PET/CT imaging and subsequently PET/MR imaging (mean delay 100 min). Patients were separated into two groups: the alpha group (14 patients) without MR coils during PET/MR imaging and the beta group (12 patients) with MR coils present (neurovascular, spine, cardiac and torso coils). All images were coregistered to the same space (PET/MR). The two PET images from PET/MR reconstructed using MRAC and CTAC were compared by voxel-based and region-based methods (with ten regions of interest, ROIs). Lesions were also compared by an experienced clinician.

Results

Body mass index and lung density showed significant differences between the alpha and beta groups. Right and left lung densities were also significantly different within each group. The percentage differences in uptake values using MRAC in relation to those using CTAC were greater in the beta group than in the alpha group (alpha group ?0.2 ± 33.6 %, R ²?=?0.98, p?<?0.001; beta group 10.31 ± 69.86 %, R ²?=?0.97, p?<?0.001).

Conclusion

In comparison to CTAC, MRAC led to underestimation of the PET values by less than 10 % on average, although some ROIs and lesions did differ by more (including the spine, lung and heart). The beta group (imaged with coils present) showed increased overall PET quantification as well as increased variability compared to the alpha group (imaged without coils). PET data reconstructed with MRAC and CTAC showed some differences, mostly in relation to air pockets, metallic implants and attenuation differences in large bone areas (such as the pelvis and spine) due to the segmentation limitation of the MRAC method.     

Investigation of the pharmacokinetics of 3′-deoxy-3′-[18F]fluorothymidine uptake in the bone marrow before and early after initiation of chemoradiation therapy in head and neck cancer

IntroductionThe kinetics of the bone marrow uptake of 3′-deoxy-3′-[¹⁸F]fluorothymidine (FLT) before and early after initiation of chemoradiation therapy was investigated in patients with head and neck cancer.MethodsFourteen subjects with head and neck cancer underwent FLT positron emission tomography (PET) at baseline and after 10 Gy of radiation therapy. Thirteen subjects also received one cycle of platinum-based chemotherapy before the second FLT PET. Kinetic parameters, including the flux constant based on compartmental analysis (K_FLT) and the Patlak constant (K_Patlak) for cervical marrow, were calculated. Standardized uptake values (SUVs) for the cervical marrow (inside the radiation field) and lumbar spine marrow (outside the radiation field) were also determined.ResultsThere was a significant drop in FLT uptake in the bone marrow inside the radiation field. Mean pretreatment uptake values for the cervical spine were SUV=3.08±0.66, K_FLT=0.045±0.016 min^?1 and K_Patlak=0.039±0.013 min^?1. After treatment, these values were SUV=0.74±0.19, K_FLT=0.011±0.005 min^?1 and K_Patlak=0.005±0.002 min^?1. Compartmental analysis revealed a significant drop in k₃ in irradiated cervical marrow. FLT uptake in the bone marrow outside the radiation field exhibited a significantly smaller decrease.ConclusionsThere is a marked decrease in FLT uptake in irradiated bone marrow after 10 Gy of radiation therapy to the head and neck. The drop in FLT uptake in irradiated marrow is due to a significant decrease in the net phosphorylation rate of FLT.     

Tumor uptake of 68Ga-DOTA-Tyr3-octreotate: animal PET studies of tumor flow and acute somatostatin receptor modulation in the CA20948 rat model

IntroductionFactors determining the in vivo uptake of radiolabeled somatostatin analogs by neuroendocrine tumors are poorly known. The aim is to evaluate in vivo tumor perfusion and regulation of somatostatin receptors (sstr) following acute exposure to octreotide, in an animal model of neuroendocrine tumor.MethodsH₂¹⁵O flow studies were performed in 8 CA20948 tumor-bearing rats and another 36 rats underwent three [⁶⁸Ga]-DOTA-Tyr³-octreotate imaging sessions at 24-h intervals. After baseline (Day 0) imaging, scanning was repeated on Day 1 after octreotide injection (175 μg/kg), with a variable delay: no injection (controls, n=7), coinjection (n=6), and octreotide injection 20 min (n=7), 2 h (n=8) and 4 h (n=8) before imaging. Repeat images without octreotide was performed at Day 2 followed by sacrifice and tumor counting.ResultsH₂¹⁵O studies failed to measure quantitative tumor perfusion in this model. On Day 1, ratio of tumor uptake to Day 0 was 1.2±0.3 in controls; 0.6±0.2 in the coinjection group; 0.9±0.2, 1.1±0.1 and 1.2±0.2 in the other groups, respectively. Uptake in the coinjection group showed a statistically significant reduction of tumor uptake (P<.0001). All groups showed increased uptake on Day 2, without statistical differences between groups. In vivo tumor counts showed good correlation with ex vivo countings (R²=0.946).ConclusionAcute exposure to unlabeled octreotide in this neuroendocrine tumor model results in a rapid recycling or resynthesis of sstr. Positron emission tomography (PET) allowed to reliably assess quantitative uptake of [⁶⁸Ga]-DOTA-Tyr³-octreotate over time in the same animal, but failed in this model to measure tumor perfusion.     

Influence of volumetric 4′-[methyl-<Superscript>11</Superscript>C]-thiothymidine PET/CT parameters for prediction of the clinical outcome of head and neck cancer patients

Objective

This prospective study compared the value of pretreatment 4′-[methyl-¹¹C]-thiothymidine (¹¹C-4DST) volumetric parameters and those of 2-deoxy-2-[18F] fluoro-d-glucose (¹⁸F-FDG) in predicting the clinical outcome in patients with head and neck squamous cell carcinoma (HNSCC).

Methods

Fifty patients with HNSCC underwent ¹¹C-4DST PET/CT and ¹⁸F-FDG PET/CT prior to anticancer therapy. ¹⁸F-FDG metabolic tumor volume (¹⁸F-FDG MTV) and total lesion glycolysis (TLG) were calculated from ¹⁸F-FDG PET, and ¹¹C-4DST MTV and total lesion proliferation (TLP) were calculated from ¹¹C-4DST PET. All parameters were measured for the primary lesion and metastatic lymph nodes. Associations between clinical factors and PET/CT parameters and prognostic value were analyzed.

Results

Receiver-operating characteristic analysis revealed that MTV, TLG, and TLP acquired from the primary lesion and metastatic lymph nodes were good parameters for predicting disease relapse and death. The area under the curves (AUCs) ranged from 0.63 to 0.71 for ¹⁸F-FDG PET/CT parameters. The AUCs of ¹¹C-4DST PET/CT parameters were larger than those of ¹⁸F-FDG (range 0.72–0.81). Univariate analysis revealed that individuals with tumors showing a high value for any PET/CT parameter were at a significantly increased risk of relapse. Upon multivariate analysis, ¹⁸F-FDG MTV, ¹¹C-4DST MTV and ¹¹C-4DST TLP were significant independent factors for relapse-free survival (P = 0.04, P = 0.0001 and P = 0.0005, respectively).

Conclusion

Pretreatment ¹¹C-4DST PET/CT volume-based parameters can provide important prognostic information about patients with HNSCC.

     

The influence of mass of [11C]-laniquidar and [11C]-N-desmethyl-loperamide on P-glycoprotein blockage at the blood-brain barrier

IntroductionAn earlier report suggested that mass amount of PET tracers could be an important factor in brain uptake mediated by P-glycoprotein. Thereby, this study investigated the influence of mass dose of laniquidar, desmethyl-loperamide and loperamide on the P-glycoprotein-mediated brain uptake of, respectively, [¹¹C]-laniquidar and [¹¹C]-N-desmethyl-loperamide ([¹¹C]-dLop).MethodsWild-type (WT) mice were injected intravenously with solutions of 5.6 MBq [¹¹C]-laniquidar (either no carrier added or 60 mg/kg laniquidar added) or with 5.0–7.4 MBq [¹¹C]-dLop (either no carrier added or 3 mg/kg desmethyl loperamide). Mice were killed, and brain and blood were collected, weighted and counted for radioactivity. Mdr1a(?/?) knockout mice were incorporated as the control group.ResultsInjection of ¹¹C-laniquidar (no carrier added) in WT mice resulted in a statistical significant lower brain uptake (0.7±0.2 %ID/g) compared to the carrier-added formulation (60 mg/kg laniquidar) (3.1±0.3 %ID/g) (P=.004), while no statistical difference could be observed between formulations of [¹¹C]-dLop. The [¹¹C]-laniquidar and [¹¹C]-dLop blood concentrations were not significantly different between the tested formulations in WT mice. In control animals, no effect of mass amount on brain uptake of both tracers could be demonstrated.ConclusionsThese results demonstrate the bivalent character of laniquidar, acting as a substrate at low doses and as a blocking agent for P-glycoprotein transport in the brain at higher doses. In comparison, no difference was observed in [¹¹C]-dLop uptake between carrier- and no-carrier-added formulations, which confirms that desmethyl-loperamide is a substrate of P-glycoprotein at the blood–brain barrier.     

Response assessment of bevacizumab in patients with recurrent malignant glioma using [18F]Fluoroethyl-l-tyrosine PET in comparison to MRI

Purpose

To investigate prospectively the potential of O-(2-[¹⁸F]fluoroethyl)-l-tyrosine (¹⁸F-FET) PET in comparison to MRI for the assessment of the response of patients with recurrent high-grade glioma (rHGG) to antiangiogenic treatment.

Methods

Ten patients with rHGG were treated biweekly with bevacizumab/irinotecan (BEV/IR). MR images and dynamic ¹⁸F-FET PET scans were obtained at baseline and at follow-up after the start of treatment (median 4.9 weeks). Using MRI treatment response was evaluated according to RANO (Response Assessment in Neuro-Oncology) criteria. For ¹⁸F-FET PET evaluation, a reduction >45?% of the metabolically active tumour volume was considered as a treatment response, with the metabolically active tumour being defined as a tumour-to-brain ratio (TBR) of ??1.6. The results of the treatment assessments were related to progression-free survival (PFS) and overall survival (OS). For further evaluation of PET data, maximum and mean TBR were calculated using region-of-interest analysis at baseline and at follow-up. Additionally, ¹⁸F-FET uptake kinetic studies were performed at baseline and at follow-up in all patients. Time?Cactivity curves were generated and the times to peak (TTP) uptake (in minutes from the beginning of the dynamic acquisition to the maximum uptake) were calculated.

Results

At follow-up, MRI showed a complete response according to RANO criteria in one of the ten patients (10?%), a partial response in five patients (50?%), and stable disease in four patients (40?%). Thus, MRI did not detect tumour progression. In contrast, ¹⁸F-FET PET revealed six metabolic responders (60?%) and four nonresponders (40?%). In the univariate survival analyses, a response detected by ¹⁸F-FET PET predicted a significantly longer PFS (median PFS, 9 vs. 3 months; P?=?0.001) and OS (median OS 23.0?months vs. 3.5 months; P?=?0.001). Furthermore, in four patients (40?%), diagnosis according to RANO criteria and by ¹⁸F-FET PET was discordant. In these patients, PET was able to detect tumour progression earlier than MRI (median time benefit 10.5?weeks; range 6?C12?weeks). At baseline and at follow-up, in nonresponders TTP was significantly shorter than in responders (baseline TTP 10?±?8?min vs. 35?±?9?min; P?=?0.002; follow-up TTP 23?±?9?min vs. 39?±?8?min; P?=?0.02). Additionally, at baseline a kinetic pattern characterized by an early peak of ¹⁸F-FET uptake followed by a constant descent was more frequently observed in the nonresponders (P?=?0.018).

Conclusion

Both standard and kinetic imaging parameters derived from¹⁸F-FET PET seem to predict BEV/IR treatment failure and thus contribute important additional information for clinical management over and above the information obtained by MRI response assessment based on RANO criteria.     

Role of 18F-FDG PET/CT in differentiation of a benign lesion and metastasis on the ribs of cancer patients

ObjectiveIncidental 18-Fluoro-2-deoxyglucose positron emission tomography (¹⁸F-FDG) uptake in the ribs is a relatively common finding on positron emission tomography/computed tomography (PET/CT) images of cancer patients. This study examined the role of ¹⁸F-FDG PET/CT in differentiating between benign lesions and metastases on the ribs.MethodsThis study included 264 lesions in 172 PET/CT cases with underlying malignancy showing newly developed indeterminate ¹⁸F-FDG rib uptake between June 2009 and May 2010. Patients with more than five FDG rib uptakes or hematologic malignancy were excluded. Malignancy was confirmed either histologically or by imaging studies, and clinical follow-up with serial images was at least 6 months. The maximum standardized uptake value (SUVmax) of the rib lesion was recorded. The FDG uptake patterns (focal or segmental; discrete or non-discrete) and CT findings (evidence of fracture, soft tissue lesions, osteoblastic and/or osteolytic lesions) were recorded.ResultsThere were 206 benign lesions and 58 metastases. The SUVmax was significantly higher in the metastatic group (3.0±1.8) than in the benign group (2.5±1.1), (P= .014). For the differential diagnosis between benign and metastatic lesions, the best SUVmax cut-off was determined to be 2.4. Significant indicators for metastasis were a segmental FDG uptake pattern (OR=10.262, 95% CI 4.151–25.371), presence of an osteoblastic/-lytic lesion (OR=22.903, 95% CI 10.468 to 50.108) and the absence of fractures on CT (OR=291.629, 95% CI 39.09–2175.666).ConclusionSUVmax alone is not sufficient to differentiate benign and metastatic rib lesions in cancer patients. The diagnostic accuracy can be further increased when findings of the CT part of PET/CT are considered.