Discovery of a Promising Fluorine-18 Positron Emission Tomography Radiotracer for Imaging Sphingosine-1-Phosphate Receptor 1 in the Brain.

Sphingosine-1-phosphate receptor 1 (S1PR1) is recognized as a novel therapeutic and diagnostic target in neurological disorders. We recently transferred the S1PR1 radioligand [11C]CS1P1 into clinical investigation for multiple sclerosis. Herein, we reported the design, synthesis and evaluation of novel F-18 S1PR1 radioligands. We combined the structural advantages of our two lead S1PR1 radioligands and synthesized 14 new S1PR1 compounds, then performed F-18 radiochemistry on the most promising compounds. Compound 6h is potent (IC50 = 8.7 nM) and selective for S1PR1. [18F]6h exhibited a high uptake in macaque brain (SUV > 3.0) and favorable brain washout pharmacokinetics in positron emission tomography (PET) study. PET blocking and displacement studies confirmed the specificity of [18F]6h in vivo. Radiometabolite analysis confirmed no radiometabolite of [18F]6h entered into the brain to confound the PET measurement. In summary, [18F]6h is a promising radioligand to image S1PR1 and worth translational clinical investigation for humans with brain disorders.

A novel 18F-labeled agonist for PET imaging of stimulator of interferon gene expression in tumor-bearing mice.

PURPOSE: Stimulator of interferon genes (STING) protein plays a vital role in the immune surveillance of tumor microenvironment. Monitoring STING expression in tumors benefits the relevant STING therapy. This study aimed to develop a novel 18F-labeled agonist, dimeric amidobenzimidazole (diABZI), and firstly evaluate the feasibility of noninvasive positron emission tomography (PET) imaging of STING expression in the tumor microenvironment. METHODS: An analog of the STING agonist NOTA-DABI was synthesized and labeled with 18F via Al18F-NOTA complexation (denoted as [18F]F-DABI). Physicochemical properties, STING protein-binding affinity, and specificity of [18F]F-DABI were evaluated using cell uptake and docking assays. In vivo small-animal PET imaging and biodistribution studies of [18F]F-DABI in tumor-bearing mice were performed to verify the pharmacokinetics and tumor targeting ability. The correlation between tumor uptake and STING expression was also analyzed. RESULTS: [18F]F-DABI was produced conveniently with high radiochemical yield (44 ± 15%), radiochemical purity (> 97%) and molar activity (15-30 GBq/µmol). In vitro binding assays demonstrated that [18F]F-DABI has a favorable affinity and specificity for STING with a KD of 12.98 ± 2.07 nM. In vivo studies demonstrated the specificity of [18F]F-DABI for PET imaging of STING expression with B16F10 tumor uptake of 10.93 ± 0.93%ID/g, which was significantly different from that of blocking groups (3.13 ± 0.88%ID/g, ***p < 0.0001). Furthermore, tumor uptake of [18F]F-DABI was well positively correlated with STING expression in different tumor types. Biodistribution results demonstrated that [18F]F-DABI was predominately uptaken in the liver and intestines, indicating its hepatobiliary elimination. CONCLUSION: This proof-of-concept study demonstrated a STING-binding radioligand for PET imaging, which could be used as a potential companion diagnostic tool for related STING-agonist therapies.

Development of 18F-Labeled Vinyl Sulfone-PSMAi Conjugates as New PET Agents for Prostate Cancer Imaging.

Radiolabeled prostate-specific membrane antigen (PSMA) ligands have been rapidly adopted as part of patient care for prostate cancer. In this study, a new series of 18F-labeled PSMA-targeting agents was developed based on the high-affinity Glu-ureido-Lys scaffold and 18F-vinyl sulfones (VSs), the tumor uptake and tumor/major organ contrast of which could be tuned by pharmacokinetic linkers within the molecules. In particular, 18F-PEG3-VS-PSMAi showed the highest tumor uptake (12.1 ± 2.2%ID/g at 0.5 h p.i.) and 18F-PEG2-VS-PSMAi showed the highest tumor-to-liver ratio (T/L = 3.7 ± 1.0, 4.8 ± 1.2, and 6.3 ± 1.1 at 0.5, 1.5, and 3 h p.i. respectively). Significantly, compared with the FDA-approved 68Ga-PSMA-11, the newly developed 18F-PEG3-VS-PSMAi has an almost double tumor uptake (P < 0.0001) when tested in the same animal model. In conclusion, 18F-VS-labeled PSMA ligands are promising PET agents with prominent tumor uptake and high contrast. The lead agents 18F-PEG2-VS-PSMAi and 18F-PEG3-VS-PSMAi warrant further evaluation in prostate cancer patients.

Novel [18F]-Labeled Meta-Bromobenzylguanidine Derivatives: Potential Positron Emission Tomography Imaging Probes for the Norepinephrine Transporter.

To develop novel norepinephrine transporter (NET)-targeting positron emission tomography (PET) probes with optimal pharmacokinetic properties, a series of meta-bromobenzylguanidine derivatives was synthesized. 4-Fluorodiethoxyethane-3-bromobenzylguanidine (compound 12) showed relatively good affinity for the NET (IC50 = 1.00 ± 0.04 µM). The corresponding radiotracer 18F-12 was prepared in high radiochemical purity (>98%) via a three-step method. The in vitro cellular uptake results demonstrated that 18F-12 was specifically taken up by NET-expressing SK-N-SH cells by the uptake-1 mechanism. Biodistribution studies in mice showed that 18F-12 exhibited high cardiac uptake (10.45 ± 0.66 %ID/g at 5 min p.i. and 6.44 ± 0.40 %ID/g at 120 min p.i.), faster liver clearance, and a lower dose of absorbed radiation than [123I]-labeled meta-iodobenzylguanidine ([123I]MIBG). Small animal PET imaging confirmed the high heart-to-background ratio of 18F-12 and the uptake-1 mechanism specific for the NET in rats, indicating its potential as a promising PET radiotracer for cardiac sympathetic nerve imaging.

Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics.

Macromolecules such as monoclonal antibodies (mAbs) are likely to experience poor tumor penetration because of their large size, and thus low drug exposure of target cells within a tumor could contribute to suboptimal responses. Given the challenge of inadequate quantitative tools to assess mAb activity within tumors, we hypothesized that measurement of accessible target levels in tumors could elucidate the pharmacologic activity of a mAb and could be used to compare the activity of different mAbs. Using positron emission tomography (PET), we measured the pharmacodynamics of immune checkpoint protein programmed-death ligand 1 (PD-L1) to evaluate pharmacologic effects of mAbs targeting PD-L1 and its receptor programmed cell death protein 1 (PD-1). For PD-L1 quantification, we first developed a small peptide-based fluorine-18-labeled PET imaging agent, [18F]DK222, which provided high-contrast images in preclinical models. We then quantified accessible PD-L1 levels in the tumor bed during treatment with anti-PD-1 and anti-PD-L1 mAbs. Applying mixed-effects models to these data, we found subtle differences in the pharmacodynamic effects of two anti-PD-1 mAbs (nivolumab and pembrolizumab). In contrast, we observed starkly divergent target engagement with anti-PD-L1 mAbs (atezolizumab, avelumab, and durvalumab) that were administered at equivalent doses, correlating with differential effects on tumor growth. Thus, we show that measuring PD-L1 pharmacodynamics informs mechanistic understanding of therapeutic mAbs targeting PD-L1 and PD-1. These findings demonstrate the value of quantifying target pharmacodynamics to elucidate the pharmacologic activity of mAbs, independent of mAb biophysical properties and inclusive of all physiological variables, which are highly heterogeneous within and across tumors and patients.

Prognostic significance of volume-based 18F-FDG PET/CT parameters and correlation with PD-L1 expression in patients with surgically resected lung adenocarcinoma.

ABSTRACT: The aim of this study was to retrospectively analyze 18F-FDG positron emission tomography/computed tomography (18F-FDG PET/CT) metabolic variables, programmed death-ligand 1 (PD-L1) and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) tumor expression, and other factors as predictors of disease-free survival (DFS) in patients with lung adenocarcinoma (LUAD) (stage IA-IIIA) who underwent surgical resection. We still lack predictor of immune checkpoint (programmed cell death-1 [PD-1]/PD-L1) inhibitors. Herein, we investigated the correlation between metabolic parameters from 18F-FDG PET/CT and PD-L1 expression in patients with surgically resected LUAD.Seventy-four patients who underwent 18F-FDG PET/CT prior to treatment were consecutively enrolled. The main 18F-FDG PET/CT-derived variables were primary tumor maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Surgical tumor specimens were analyzed for PD-L1 and p-STAT3 expression using immunohistochemistry. Correlations between immunohistochemistry results and 18F-FDG PET/CT-derived variables were compared. Associations of PD-L1 and p-STAT3 tumor expression, 18F-FDG PET/CT-derived variables, and other factors with DFS in resected LUAD were evaluated.All tumors were FDG-avid. The cutoff values of low and high SUVmax, MTV, and TLG were 12.60, 14.87, and 90.85, respectively. The results indicated that TNM stage, PD-L1 positivity, and high 18F-FDG PET/CT metabolic volume parameters (TLG ≥90.85 or MTV ≥14.87) were independent predictors of worse DFS in resected LUAD. No 18F-FDG metabolic parameters associated with PD-L1 expression were observed (chi-square test), but we found that patients with positive PD-L1 expression have significantly higher SUVmax (P = .01), MTV (P = .00), and TLG (P = .00) than patients with negative PD-L1 expression.18F-FDG PET/CT metabolic volume parameters (TLG ≥90.85 or MTV ≥14.87) were more helpful in prognostication than the conventional parameter (SUVmax), PD-L1 expression was an independent predictor of DFS in patients with resected LUAD. Metabolic parameters on 18F-FDG PET/CT have a potential role for 18F-FDG PET/CT in selecting candidate LUAD for treatment with checkpoint inhibitors.

First-in-Human Evaluation of Positron Emission Tomography/Computed Tomography With [18F]FB(ePEG12)12-Exendin-4: A Phase 1 Clinical Study Targeting GLP-1 Receptor Expression Cells in Pancreas.

Pancreatic ß-cell mass (BCM) has a central importance in the pathophysiology of diabetes mellitus. Recently, pancreatic ß-cell-specific imaging, especially positron emission tomography (PET) with exendin-based probes, has emerged for non-invasive evaluation of BCM. We developed a novel exendin-based probe labeled with fluorine-18, [18F]FB(ePEG12)12-exendin-4 (18F-Ex4) for PET imaging. We subsequently conducted a first-in-human phase 1 study of 18F-Ex4 PET/computed tomography (CT) and investigated the safety and utility for visualizing the pancreas. Six healthy male subjects were enrolled in this study. A low dose (37.0 MBq) of 18F-Ex4 PET/CT was administered (first cohort: n = 2), and subsequently a higher dose (74.0 MBq) was administered (second cohort: n = 4). In the first and second cohorts, 38.6 ± 4.8 and 71.1 ± 4.8 MBq of 18F-Ex4 were administered, respectively. No serious adverse events were observed in both groups. Only one participant in the first cohort showed transient hypoglycemia during the PET scans. 18F-Ex4 PET/CT successfully visualized the pancreas in all participants. The mean standardized uptake value of the pancreas was found to be higher than that in the surrounding organs, except for the bladder and kidney, during the observation. Dosimetry analyses revealed the effective systemic doses of 18F-Ex4 as 0.0164 ± 0.0019 mSv/MBq (first cohort) and 0.0173 ± 0.0020 mSv/MBq (second cohort). 18F-Ex4 PET/CT demonstrated the safety and utility for non-invasive visualization of the pancreas in healthy male subjects. 18F-Ex4 is promising for clinical PET imaging targeting pancreatic ß cells.

Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain.

Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.

Evaluation of Class IIa Histone Deacetylases Expression and In Vivo Epigenetic Imaging in a Transgenic Mouse Model of Alzheimer's Disease.

Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and memory formation, and its aberrant expression has been linked to cognitive disorders, including Alzheimer's disease (AD). This study aimed to investigate the role of class IIa HDAC expression in AD and monitor it in vivo using a novel radiotracer, 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]TFAHA). A human neural cell culture model with familial AD (FAD) mutations was established and used for in vitro assays. Positron emission tomography (PET) imaging with [18F]TFAHA was performed in a 3xTg AD mouse model for in vivo evaluation. The results showed a significant increase in HDAC4 expression in response to amyloid-ß (Aß) deposition in the cell model. Moreover, treatment with an HDAC4 selective inhibitor significantly upregulated the expression of neuronal memory-/synaptic plasticity-related genes. In [18F]TFAHA-PET imaging, whole brain or regional uptake was significantly higher in 3xTg AD mice compared with WT mice at 8 and 11 months of age. Our study demonstrated a correlation between class IIa HDACs and Aßs, the therapeutic benefit of a selective inhibitor, and the potential of using [18F]TFAHA as an epigenetic radiotracer for AD, which might facilitate the development of AD-related neuroimaging approaches and therapies.

Minimally invasive quantification of cerebral P2X7R occupancy using dynamic [18F]JNJ-64413739 PET and MRA-driven image derived input function.

[18F]JNJ-64413739 has been evaluated as PET-ligand for in vivo quantification of purinergic receptor subtype 7 receptor (P2X7R) using Logan graphical analysis with a metabolite-corrected arterial plasma input function. In the context of a P2X7R PET dose occupancy study, we evaluated a minimally invasive approach by limiting arterial sampling to baseline conditions. Meanwhile, post dose distribution volumes (VT) under blocking conditions were estimated by combining baseline blood to plasma ratios and metabolite fractions with an MR angiography driven image derived input function (IDIF). Regional postdose VT,IDIF values were compared with corresponding VT,AIF estimates using a arterial input function (AIF), in terms of absolute values, test-retest reliability and receptor occupancy. Compared to an invasive AIF approach, postdose VT,IDIF values and corresponding receptor occupancies showed only limited bias (Bland-Altman analysis: 0.06 ± 0.27 and 3.1% ± 6.4%) while demonstrating a high correlation (Spearman ρ = 0.78 and ρ = 0.98 respectively). In terms of test-retest reliability, regional intraclass correlation coefficients were 0.98 ± 0.02 for VT,IDIF compared to 0.97 ± 0.01 for VT,AIF. These results confirmed that a postdose IDIF, guided by MR angiography and using baseline blood and metabolite data, can be considered for accurate [18F]JNJ-64413739 PET quantification in a repeated PET study design, thus avoiding multiple invasive arterial sampling and increasing dosing flexibility.

Identify glioma recurrence and treatment effects with triple-tracer PET/CT.

BACKGROUND: Differential diagnosis of tumour recurrence (TuR) from treatment effects (TrE), mostly induced by radiotherapy and chemotherapy, is still difficult by using conventional computed tomography (CT) or magnetic resonance (MR) imaging. We have investigated the diagnostic performance of PET/CT with 3 tracers, 13N-NH3, 18F-FDOPA, and 18F-FDG, to identify TuR and TrE in glioma patients following treatment. METHODS: Forty-three patients with MR-suspected recurrent glioma were included. The maximum and mean standardized uptake values (SUVmax and SUVmean) of the lesion and the lesion-to-normal grey-matter cortex uptake (L/G) ratio were obtained from each tracer PET/CT. TuR or TrE was determined by histopathology or clinical MR follow-up for at least 6 months. RESULTS: In this cohort, 34 patients were confirmed to have TuR, and 9 patients met the diagnostic standard of TrE. The SUVmax and SUVmean of 13N-NH3 and 18F-FDOPA PET/CT at TuR lesions were significantly higher compared with normal brain tissue (13N-NH3 0.696 ± 0.558, 0.625 ± 0.507 vs 0.486 ± 0.413; 18F-FDOPA 0.455 ± 0.518, 0.415 ± 0.477 vs 0.194 ± 0.203; both P < 0.01), but there was no significant difference in 18F-FDG (6.918 ± 3.190, 6.016 ± 2.807 vs 6.356 ± 3.104, P = 0.290 and 0.493). L/G ratios of 13N-NH3 and 18F-FDOPA were significantly higher in TuR than in TrE group (13N-NH3, 1.573 ± 0.099 vs 1.025 ± 0.128, P = 0.008; 18F-FDOPA, 2.729 ± 0.131 vs 1.514 ± 0.141, P < 0.001). The sensitivity, specificity and AUC (area under the curve) by ROC (receiver operating characteristic) analysis were 57.7%, 100% and 0.803, for 13N-NH3; 84.6%, 100% and 0.938, for 18F-FDOPA; and 80.8%, 100%, and 0.952, for the combination, respectively. CONCLUSION: Our results suggest that although multiple tracer PET/CT may improve differential diagnosis efficacy, for glioma TuR from TrE, 18F-FDOPA PET-CT is the most reliable. The combination of 18F-FDOPA and 13N-NH3 does not increase the diagnostic efficiency, while 18F-FDG is not worthy for differential diagnosis of glioma TuR and TrE.

Effect of age on brain metabotropic glutamate receptor subtype 5 measured with [18F]FPEB PET.

OBJECTIVE: Metabotropic glutamate receptor subtype 5 (mGluR5) is integral to the brain glutamatergic system and cognitive function. This study investigated whether aging is associated with decreased brain mGluR5 availability. METHODS: Cognitively normal participants (n = 45), aged 18 to 84 years, underwent [18F]FPEB positron emission tomography scans to quantify brain mGluR5. Distribution volume (VT) was computed using a venous or arterial input function and equilibrium modeling from 90 to 120 min. In the primary analysis, the association between age and VT in the hippocampus and association cortex was evaluated using a linear mixed model. Exploratory analyses assessed the association between age and VT in multiple brain regions. The contribution of gray matter tissue alterations and partial volume effects to associations with age was also examined. RESULTS: In the primary analysis, older age was associated with lower [18F]FPEB binding to mGluR5 (P = 0.026), whereas this association was not significant after gray matter masking or partial volume correction to account for age-related tissue loss. Post hoc analyses revealed an age-related decline in mGluR5 availability in the hippocampus of 4.5% per decade (P = 0.007) and a non-significant trend in the association cortex (P = 0.085). An exploratory analysis of multiple brain regions revealed broader inverse associations of age with mGluR5 availability, but not after partial volume correction. CONCLUSION: Reductions in mGluR5 availability with age appear to be largely mediated by tissue loss. Quantification of [18F]FPEB binding to mGluR5 may expand our understanding of age-related molecular changes and the relationship with brain tissue loss.

Synthesis and Biological Evaluation of [18F]FECNT-d4 as a Novel PET Agent for Dopamine Transporter Imaging.

PURPOSE: The dopamine transporter (DAT) is a marker of the occurrence and development of Parkinson's disease (PD) and other diseases with nigrostriatal degeneration. 2ß-Carbomethoxy-3ß-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl)nortropane ([18F]FECNT), an 18F-labelled tropane derivative, was reported to be a useful positron-emitting probe for DAT. However, the rapid formation of brain-penetrating radioactive metabolites is an impediment to the proper quantitation of DAT in PET studies with [18F]FECNT. Deuterium-substituted analogues have presented better in vivo stability to reduce metabolites. This study aimed to synthesize a deuterium-substituted DAT radiotracer, [18F]FECNT-d4, and to make a preliminary investigation of its properties as a DAT tracer in vivo. PROCEDURES: The ligand [18F]FECNT-d4 was obtained by one-step radiolabelling reaction. The lipophilicity was measured by the shake-flask method. Binding properties of [18F]FECNT-d4 were estimated by in vitro binding assay, biodistribution, and microPET imaging in rats. In vivo stability of [18F]FECNT-d4 was estimated by radio-HPLC. RESULTS: [18F]FECNT-d4 was synthesized at an average activity yield of 46 ± 17 % (n = 15) and the molar activity was 67 ± 12 GBq/µmol. The deuterated tracer showed suitable lipophilicity and the ability to penetrate the blood-brain barrier (brain uptake of 1.72 % ID at 5 min). [18F]FECNT-d4 displayed a high binding affinity for DAT comparable to that of [18F]FECNT in rat striatum homogenates. Biodistribution results in normal rats showed that [18F]FECNT-d4 exhibited a higher ratio of the target to non-target (striatum/cerebellum) at 15 min post administration (5.00 ± 0.44 vs 3.84 ± 0.24 for [18F]FECNT-d4 vs [18F]FECNT). MicroPET imaging studies of [18F]FECNT-d4 in normal rats showed that the ligand selectively localized to DAT-rich striatal regions and the accumulation could be blocked with DAT inhibitor. Furthermore, in the unilateral PD model rat, a significant reduction of the signal was found in the lesioned side relative to the unlesioned side. Striatal standardized uptake value of [18F]FECNT-d4 remained ~4.02 in the striatum between 5 and 20 min, whereas that of [18F]FECNT fell rapidly from 4.11 to 2.95. Radio-HPLC analysis of the plasma demonstrated better in vivo stability of [18F]FECNT-d4 than [18F]FECNT. CONCLUSION: The deuterated compound [18F]FECNT-d4 may serve as a promising PET imaging agent to assess DAT-related disorders.

Para-chloro-2-[18F]fluoroethyl-etomidate: A promising new PET radiotracer for adrenocortical imaging.

Introduction: [11C]Metomidate ([11C]MTO), the methyl ester analogue of etomidate, was developed as a positron emission tomography (PET) radiotracer for adrenocortical tumours and has also been suggested for imaging in primary aldosteronism (PA). A disadvantage of [11C]MTO is the rather high non-specific binding in the liver, which impacts both visualization and quantification of the uptake in the right adrenal gland. Furthermore, the short 20-minute half-life of carbon-11 is a logistic challenge in the clinical setting. Objectives: The aim of this study was to further evaluate the previously published fluorine-18 (T1/2=109.5 min) etomidate analogue, para-chloro-2-[18F]fluoroethyl etomidate; [18F]CETO, as an adrenal PET tracer. Methods: In vitro experiments included autoradiography on human and cynomolgus monkey (non-human primate, NHP) tissues and binding studies on adrenal tissue from NHPs. In vivo studies with [18F]CETO in mice, rats and NHP, using PET and CT/MRI, assessed biodistribution and binding specificity in comparison to [11C]MTO. Results: The binding of [18F]CETO in the normal adrenal cortex, as well as in human adrenocortical adenomas and adrenocortical carcinomas, was shown to be specific, both in vitro (in humans) and in vivo (in rats and NHP) with an in vitro Kd of 0.66 nM. Non-specific uptake of [18F]CETO in NHP liver was found to be low compared to that of [11C]MTO. Conclusions: High specificity of [18F]CETO to the adrenal cortex was demonstrated, with in vivo binding properties qualitatively surpassing those of [11C]MTO. Non-specific binding to the liver was significantly lower than that of [11C]MTO. [18F]CETO is a promising new PET tracer for imaging of adrenocortical disease and should be evaluated further in humans.

Design, Synthesis, Biological Evaluation, and Molecular Docking of 2,4-Diaminopyrimidine Derivatives Targeting Focal Adhesion Kinase as Tumor Radiotracers.

There are two important topics in the field of cancer research: one is targeted molecular therapy and the other is tumor molecular imaging. Focal adhesion kinase (FAK) is considered as an attractive target for oncologic diagnosis and therapy. A series of 2,4-diaminopyrimidine derivatives were labeled with 18F to study their biological properties and their potential as positron emission tomography tumor imaging agents. They inhibited the activity of FAK with IC50 values in the wide range of 0.6-2164 nM, among which the IC50 of Q6 was 3.2 nM. For the biodistribution in S180-bearing mice, the corresponding [18F]Q6 was relatively good, with the highest uptake of 3.35 ± 0.32 % ID/g at 30 min postinjection, with a tumor/muscle ratio of 2.08 and a tumor/bone ratio of 2.48. Accordingly, [18F]Q6 was considered as a potential PET imaging agent for tumor diagnosis.

Assessment of quantitative [18F]Sodium fluoride PET measures of knee subchondral bone perfusion and mineralization in osteoarthritic and healthy subjects.

OBJECTIVE: Molecular information derived from dynamic [18F]sodium fluoride ([18F]NaF) PET imaging holds promise as a quantitative marker of bone metabolism. The objective of this work was to evaluate physiological mechanisms of [18F]NaF uptake in subchondral bone of individuals with and without knee osteoarthritis (OA). METHODS: Eleven healthy volunteers and twenty OA subjects were included. Both knees of all subjects were scanned simultaneously using a 3T hybrid PET/MRI system. MRI MOAKS assessment was performed to score the presence and size of osteophytes, bone marrow lesions, and cartilage lesions. Subchondral bone kinetic parameters of bone perfusion (K1), tracer extraction fraction, and total tracer uptake into bone (Ki) were evaluated using the Hawkins 3-compartment model. Measures were compared between structurally normal-appearing bone regions and those with structural findings. RESULTS: Mean and maximum SUV and kinetic parameters Ki, K1, and extraction fraction were significantly different between Healthy subjects and subjects with OA. Between-group differences in metabolic parameters were observed both in regions where the OA group had degenerative changes as well as in regions that appeared structurally normal. CONCLUSIONS: Results suggest that bone metabolism is altered in OA subjects, including bone regions with and without structural findings, compared to healthy subjects. Kinetic parameters of [18F]NaF uptake in subchondral bone show potential to quantitatively evaluate the role of bone physiology in OA initiation and progression. Objective measures of bone metabolism from [18F]NaF PET imaging can complement assessments of structural abnormalities observed on MRI.

Non-invasive Standardised Uptake Value for Verification of the Use of Previously Validated Reference Region for [18F]Flortaucipir and [18F]Florbetapir Brain PET Studies.

PURPOSE: The simplified reference tissue model (SRTM) is commonly applied for the quantification of brain positron emission tomography (PET) studies, particularly because it avoids arterial cannulation. SRTM requires a validated reference region which is obtained by baseline-blocking or displacement studies. Once a reference region is validated, the use should be verified for each new subject. This verification normally requires volume of distribution (VT) of a reference region. However, performing dynamic scanning and arterial sampling is not always possible, specifically in elderly subjects and in advanced disease stages. The aim of this study was to investigate the use of non-invasive standardised uptake value (SUV) approaches, in comparison to VT, as a verification of the previously validated grey matter cerebellum reference region for [18F]flortaucipir and [18F]florbetapir PET imaging in Alzheimer's disease (AD) patients and controls. PROCEDURES: Dynamic 130-min [18F]flortaucipir PET scans obtained from nineteen subjects (10 AD patients) and 90-min [18F]florbetapir dynamic scans obtained from fourteen subjects (8 AD patients) were included. Regional VT's were estimated for both tracers and were considered the standard verification of the previously validated reference region. Non-invasive SUVs corrected for body weight (SUVBW), lean body mass (SUL), and body surface area (SUVBSA) were obtained by using later time intervals of the dynamic scans. Simulations were also performed to assess the effect of flow and specific binding (BPND) on the SUVs. RESULTS: A low SUV corresponded well with a low VT for both [18F]flortaucipir and [18F]florbetapir. Simulation confirmed that SUVs were only slightly affected by flow changes and that increases in SUV were predominantly determined by the presence of specific binding. CONCLUSIONS: In situations where dynamic scanning and arterial sampling is not possible, a low SUV(80-100 min) for [18F]flortaucipir and a low SUV(50-70 min) for [18F]florbetapir may be used as indication for absence of specific binding in the grey matter cerebellum reference region.

18F-Sodium fluoride uptake is associated with severity of atherosclerotic stenosis in stable ischemic heart disease.

BACKGROUND: Increased uptake of 18F-Sodium fluoride (18F-NaF) PET has potential to identify atherosclerotic plaques that are vulnerable to rupture. Whether 18F-NaF PET can evaluate the significance of atherosclerotic plaque in patients with stable coronary artery disease is less clear. We evaluated 18F-NaF PET uptake in coronary arteries in patients without acute coronary artery syndrome to determine the association of 18F-NaF signal uptake with severity of coronary stenosis. METHODS AND RESULTS: We retrospectively identified 114 patients who received both regadenoson stress 82Rb myocardial perfusion PET and 18F-NaF PET study with an average interval of 5 months. Out of this cohort, forty-one patients underwent invasive coronary angiography. In a patient-based analysis, patients with ischemic regadenoson stress 82Rb PET had significantly higher coronary 18F-NaF uptake than patients with normal myocardial perfusion (P < .01). Among the 41 patients who underwent coronary angiography, per-vessel 18F-NaF uptake in both obstructive and nonobstructive coronary arteries was significantly higher than in normal coronary arteries (P < .05) regardless of the severity of coronary calcification. There was poor correlation between calcification and 18F-NaF uptake in coronary arteries (r = 0.41) CONCLUSION: Coronary arterial 18F-NaF uptake is associated with coronary stenosis severity in patients with stable coronary artery disease. 18F-NaF PET studies may be useful for characterizing coronary atherosclerotic plaques.

Cell proliferation detected using [18F]FLT PET/CT as an early marker of abdominal aortic aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a focal aortic dilatation progressing towards rupture. Non-invasive AAA-associated cell proliferation biomarkers are not yet established. We investigated the feasibility of the cell proliferation radiotracer, fluorine-18-fluorothymidine ([18F]FLT) with positron emission tomography/computed tomography (PET/CT) in a progressive pre-clinical AAA model (angiotensin II, AngII infusion). METHODS AND RESULTS: Fourteen-week-old apolipoprotein E-knockout (ApoE-/-) mice received saline or AngII via osmotic mini-pumps for 14 (n = 7 and 5, respectively) or 28 (n = 3 and 4, respectively) days and underwent 90-minute dynamic [18F]FLT PET/CT. Organs were harvested from independent cohorts for gamma counting, ultrasound scanning, and western blotting. [18F]FLT uptake was significantly greater in 14- (n = 5) and 28-day (n = 3) AAA than in saline control aortae (n = 5) (P < 0.001), which reduced between days 14 and 28. Whole-organ gamma counting confirmed greater [18F]FLT uptake in 14-day AAA (n = 9) compared to saline-infused aortae (n = 4) (P < 0.05), correlating positively with aortic volume (r = 0.71, P < 0.01). Fourteen-day AAA tissue showed increased expression of thymidine kinase-1, equilibrative nucleoside transporter (ENT)-1, ENT-2, concentrative nucleoside transporter (CNT)-1, and CNT-3 than 28-day AAA and saline control tissues (n = 3 each) (all P < 0.001). CONCLUSIONS: [18F]FLT uptake is increased during the active growth phase of the AAA model compared to saline control mice and late-stage AAA.

Temporal relationship between 18F-sodium fluoride uptake in the abdominal aorta and evolution of CT-verified vascular calcification.

BACKGROUND: Fluoride-18 sodium fluoride (18F-NaF) localizes in microcalcifications in atheroma. The microcalcifications may aggregate, passing the resolution threshold to visualize on computed tomography (CT). We evaluated serial NaF positron emission tomography (PET)-CT scans to determine the temporal relationship between vascular NaF uptake and CT evident calcification in the abdominal aorta. METHODS: Prostate cancer patients who had at least 3 NaF PET-CT scans over at least 1.5 years were retrospectively enrolled. Regions of interest were traced in the abdominal aorta on both PET and CT images, excluding skeletal NaF activity. The maximum standardized uptake value (SUVmax) of NaF and the density and volume of calcium (exceeding 130 HU) were summed and divided by the number of slices to produce the SUVmax/slice and the mm3·slice-1 of calcium. RESULTS: Of 437 patients, 45 patients met criteria. NaF uptake waxed and waned between scans, while the calcium volume plateaued or increased over time. NaF uptake correlated with calcium volume on the baseline scan (P = .60, < .0001†) and calcium volume increment, especially from 1.0 to 1.5 years (r = .79, P < .0001†). Patients with persistently high NaF uptake showed a higher calcium volume increment (0-1.5 years) than patients with low or transiently high NaF uptake. CONCLUSIONS: Abdominal aortic NaF uptake varied over time. NaF uptake on the baseline scans and high NaF uptake on the serial scans preceded an increase in calcium volume, especially by 1.0-1.5 years. Persistently high NaF uptake was associated with a greater increment in calcium volume than patients with transiently elevated or persistently low fluoride uptake.