STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [18F]FLT PET imaging.

Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT). Accordingly, IFN treatment up-regulates cancer cell [18F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling-dependent TYMP expression in PDAC cells and increase tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist-based therapies in PDAC and possibly other malignancies characterized by elevated STING expression.

Ultrasensitive detection of malignant melanoma using PET molecular imaging probes.

Malignant melanoma has one of the highest mortality rates of any cancer because of its aggressive nature and high metastatic potential. Clinical staging of the disease at the time of diagnosis is very important for the prognosis and outcome of melanoma treatment. In this study, we designed and synthesized the 18F-labeled pyridine-based benzamide derivatives N-(2-(dimethylamino)ethyl)-5-[18F]fluoropicolinamide ([18F]DMPY2) and N-(2-(dimethylamino)ethyl)-6-[18F]fluoronicotinamide ([18F]DMPY3) to detect primary and metastatic melanoma at an early stage and evaluated their performance in this task. [18F]DMPY2 and [18F]DMPY3 were synthesized by direct radiofluorination of the bromo precursor, and radiochemical yields were ∼15-20%. Cell uptakes of [18F]DMPY2 and [18F]DMPY3 were >103-fold and 18-fold higher, respectively, in B16F10 (mouse melanoma) cells than in negative control cells. Biodistribution studies revealed strong tumor uptake and retention of [18F]DMPY2 (24.8% injected dose per gram of tissue [ID/g] at 60 min) and [18F]DMPY3 (11.7%ID/g at 60 min) in B16F10 xenografts. MicroPET imaging of both agents demonstrated strong tumoral uptake/retention and rapid washout, resulting in excellent tumor-to-background contrast in B16F10 xenografts. In particular, [18F]DMPY2 clearly visualized almost all metastatic lesions in lung and lymph nodes, with excellent image quality. [18F]DMPY2 demonstrated a significantly higher tumor-to-liver ratio than [18F]fluorodeoxyglucose ([18F]FDG) and the previously reported benzamide tracers N-[2-(diethylamino)-ethyl]-5-[18F]fluoropicolinamide ([18F]P3BZA) and N-[2-(diethylamino)-ethyl]-4-[18F]fluorobenzamide ([18F]FBZA) in B16F10-bearing or SK-MEL-3 (human melanoma)-bearing mice. In conclusion, [18F]DMPY2 might have strong potential for the diagnosis of early stage primary and metastatic melanoma using positron emission tomography (PET).

18F-Sodium Fluoride Positron Emission Tomography Activity Predicts the Development of New Coronary Artery Calcifications.

OBJECTIVE: The coronary calcium score (CCS) predicts cardiovascular disease risk in individuals with diabetes, and rate of progression of CCS is an additional and incremental marker of risk. 18F-sodium fluoride positron emission tomography (18F-NaF PET) detects early and active calcifications within the vasculature. We aimed to ascertain the relationship between 18F-NaF PET activity and CCS progression in patients with diabetes. Approach and Results: We identified individuals between 50 and 80 years with diabetes and no history of clinical coronary artery disease. Those with a CCS ≥10 were invited to undergo 18F-NaF PET scanning and then repeat CCS >2 years later. 18F-NaF PET and CCS analysis were performed on a per-coronary and a per-patient level. We compared the proportion of CCS progressors in 18F-NaF PET-positive versus 18F-NaF PET-negative coronary arteries. Forty-one participants with 163 coronary arteries underwent follow-up CCS 2.8±0.5 years later. 18F-NaF PET-positive coronary arteries (n=52) were more likely to be CCS progressors, compared with negative coronary arteries (n=111; 86.5% versus 52.3%, P<0.001). Adjusting for baseline CCS, 18F-NaF PET-positive disease was an independent predictor of subsequent CCS progression (odds ratio, 2.92 [95% CI, 1.32-6.45], P=0.008). All subjects (100%, 15/15) with ≥2 18F-NaF-positive coronary arteries progressed in CCS. CONCLUSIONS: In subjects with diabetes, 18F-NaF PET positivity at baseline, independently predicted the progression of calcifications within the coronary arteries 2.8 years later. These findings suggest 18F-NaF PET may be a promising technique for earlier identification of patients at higher risk of cardiovascular events.

Positron emission tomography reporter gene strategy for use in the central nervous system.

There is a growing need for monitoring or imaging gene therapy in the central nervous system (CNS). This can be achieved with a positron emission tomography (PET) reporter gene strategy. Here we report the development of a PET reporter gene system using the PKM2 gene with its associated radiotracer [18F]DASA-23. The PKM2 reporter gene was delivered to the brains of mice by adeno-associated virus (AAV9) via stereotactic injection. Serial PET imaging was carried out over 8 wk to assess PKM2 expression. After 8 wk, the brains were excised for further mRNA and protein analysis. PET imaging at 8 wk post-AAV delivery showed an increase in [18F]DASA-23 brain uptake in the transduced site of mice injected with the AAV mice over all controls. We believe PKM2 shows great promise as a PET reporter gene and to date is the only example that can be used in all areas of the CNS without breaking the blood-brain barrier, to monitor gene and cell therapy.

[18F]Atorvastatin Pharmacokinetics and Biodistribution in Healthy Female and Male Rats.

Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that are widely used to prevent cardiovascular diseases. However, a series of pleiotropic mechanisms have been associated with statins, particularly with atorvastatin. Therefore, the assessment of [18F]atorvastatin kinetics with positron emission tomography (PET) may elucidate the mechanism of action of statins and the impact of sexual dimorphism, which is one of the most debated interindividual variations influencing the therapeutic efficacy. [18F]Atorvastatin was synthesized via a previously optimized 18F-deoxyfluorination strategy, used for preclinical PET studies in female and male Wistar rats (n = 7 for both groups), and for subsequent ex vivo biodistribution assessment. PET data were fitted to several pharmacokinetic models, which allowed for estimating relevant kinetic parameters. Both PET imaging and biodistribution studies showed negligible uptake of [18F]atorvastatin in all tissues compared with the primary target organ (liver), excretory pathways (kidneys and small intestine), and stomach. Uptake of [18F]atorvastatin was 38 ± 3% higher in the female liver than in the male liver. The irreversible 2-tissue compartment model showed the best fit to describe [18F]atorvastatin kinetics in the liver. A strong correlation (R2 > 0.93) between quantitative Ki (the radiotracer's unidirectional net rate of influx between compartments) and semi-quantitative liver's SUV (standard uptake value), measured between 40 to 90 min, showed potential to use the latter parameter, which circumvents the need for blood sampling as a surrogate of Ki for monitoring [18F]atorvastatin uptake. Preclinical assays showed faster uptake and clearance for female rats compared to males, seemingly related to a higher efficiency for exchanges between the arterial input and the hepatic tissue. Due to the slow [18F]atorvastatin kinetics, equilibrium between the liver and plasma concentration was not reached during the time frame studied, making it difficult to obtain sufficient and accurate kinetic information to quantitatively characterize the radiotracer pharmacokinetics over time. Nevertheless, the reported results suggest that the SUV can potentially be used as a simplified measure, provided all scans are performed at the same time point. Preclinical PET-studies with [18F]atorvastatin showed faster uptake and clearance in female compared to male rats, apparently related to higher efficiency for exchange between arterial blood and hepatic tissue.

Positron Emission Tomography Imaging of Autotaxin in Thyroid and Breast Cancer Models Using [18F]PRIMATX.

Autotaxin (ATX) is a secreted enzyme responsible for producing lysophosphatidic acid (LPA). The ATX/LPA signaling axis is typically activated in wound healing and tissue repair processes. The ATX/LPA axis is highjacked and upregulated in the progression and persistence of several chronic inflammatory diseases, including cancer. As ATX inhibitors are now progressing to clinical testing, innovative diagnostic tools such as positron emission tomography (PET) are needed to measure ATX expression in vivo accurately. The radiotracer, [18F]PRIMATX, was recently developed and tested for PET imaging of ATX in vivo in a murine melanoma model. The goal of the present work was to further validate [18F]PRIMATX as a PET imaging agent by analyzing its in vivo metabolic stability and suitability for PET imaging of ATX in models of human 8305C thyroid tumor and murine 4T1 breast cancer. [18F]PRIMATX displayed favorable metabolic stability in vivo (65% of intact radiotracer after 60 min p.i.) and provided sufficient tumor uptake profiles in both tumor models. Radiotracer uptake could be blocked by 8-12% in 8305C thyroid tumors in the presence of ATX inhibitor AE-32-NZ70 as determined by PET and ex vivo biodistribution analyses. [18F]PRIMATX also showed high brain uptake, which was reduced by 50% through the administration of ATX inhibitor AE-32-NZ70. [18F]PRIMATX is a suitable radiotracer for PET imaging of ATX in the brain and peripheral tumor tissues.

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.

18F-Sodium Fluoride (18F-NaF) for Imaging Microcalcification Activity in the Cardiovascular System.

Accumulating preclinical and clinical evidence suggests that calcification is one of the body's primary responses to injury and a key pathological feature of cardiovascular disease. Calcification activity can now be imaged using 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) in combination with either computed tomography or magnetic resonance. These techniques allow visualization of calcification activity and, therefore, provide different information to the established macroscopic calcium imaged with computed tomography. Indeed, 18F-NaF PET has been used to investigate a wide range of valvular conditions, including aortic stenosis, mitral annular calcification, and bioprosthetic valve disease, as well as vascular conditions, including abdominal aortic aneurysm disease, coronary, and carotid atherosclerosis, peripheral vascular disease, and erectile dysfunction. In this brief review, we will focus on how 18F-NaF PET has improved our pathophysiological understanding of cardiovascular calcification and how it can be used as a marker of vascular calcification, providing a useful tool that can be utilized in clinical trials investigating the prediction of both disease progression and clinical events. Finally, we will discuss how 18F-NaF might be employed clinically to improve patient assessment and to guide decision-making.

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.

Tetrazine-TCO Ligation: A Potential Simple Approach to Improve Tumor Uptake through Enhanced Blood Circulation.

Targeted imaging via peptides has been extensively investigated for both diagnostic and therapeutic applications. However, peptides can be cleared out from the blood circulation quickly, leading to only moderate to low accumulation in regions of interest. Previously, 18F-sTCO-DiPhTz-RGDyK demonstrated relatively high blood retention with increased tumor uptake at the late time point (5.3 ± 0.4 and 8.9 ± 0.5%ID/g tumor uptake at 1 h p.i. and 4 h p.i., respectively). In this study, we aim to develop a novel platform based on TCO/tetrazine ligation that could be used not only to label the peptides with F-18 for PET but also to lead to increased or persistent tumor uptake potentially due to enhanced blood circulation of the labeled peptides. We first constructed systems containing different combinations of TCOs/tetrazines and found that the tetrazine moiety played a more important role to facilitate the enhanced blood circulation compared with TCO moiety. Four clinically relevant peptides including NT20.3, RGD, BBN, and exendin-4 were then evaluated, and the increased tumor uptake at a late time point was demonstrated by the combination of 18F-sTCO-DiPhTz system to NT20.3, RGD, and exendin-4. The plasma binding components of the PET agents were investigated by electrophoresis and autoradiography and indicated that transferrin and hemopexin could be the major proteins in blood plasma for binding with 18F-sTCO-DiPhTz conjugates. In summary, we have discovered a TCO/tetrazine system that could not only be used for PET probe construction but also potentially improve the tumor uptake and retention of fast-clearing peptides. Although additional binding experiments are still needed for some of the constructs, the promising preliminary result suggested that this strategy may be used to convert fast-clearing bioligands into relatively long circulating agents with enhanced tumor uptake/retention for either imaging or therapy applications.

Comparison of Al18F- and 68Ga-labeled NOTA-PEG4-LLP2A for PET imaging of very late antigen-4 in melanoma.

Malignant melanoma is an aggressive cancer with poor prognosis. Very late antigen-4 (VLA-4) is overexpressed in melanoma and many other tumors, making it an attractive target for developing molecular diagnostic and therapeutic agents. We compared Al18F- and 68Ga-labeled LLP2A peptides for PET imaging of VLA-4 expression in melanoma. The peptidomimetic ligand LLP2A was modified with chelator 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA), and the resulting NOTA-PEG4-LLP2A peptide was then radiolabeled with Al18F or 68Ga. The two labeled peptides were assayed for in vitro and in vivo VLA-4 targeting efficiency. Good Al18F and 68Ga radiolabeling yields were achieved, and the resulting PET tracers showed good serum stability. In the in vivo evaluation of the B16F10 xenograft mouse model, both tracers exhibited high accumulation with good contrast in static PET images. Compared with 68Ga-NOTA-PEG4-LLP2A, Al18F-NOTA-PEG4-LLP2A resulted in relatively higher background, including higher liver uptake (1 h: 20.1 ± 2.6 vs. 15.3 ± 1.7%ID/g, P < 0.05; 2 h: 11.0 ± 1.2 vs. 8.0 ± 0.8%ID/g, P < 0.05) and lower tumor-to-blood ratios (2.5 ± 0.4 vs. 3.3 ± 0.5 at 1 h, P < 0.05; 5.1 ± 0.9 vs. 7.3 ± 0.6 at 2 h, P < 0.01) at some time points. The results obtained from the mice blocked with unlabeled peptides and VLA-4-negative A375 xenografts groups confirmed the high specificity of the developed tracers. Despite the relatively high liver uptake, both Al18F-NOTA-PEG4-LLP2A and 68Ga-NOTA-PEG4-LLP2A exhibited high VLA-4 targeting efficacy with comparable in vivo performance, rendering them promising candidates for imaging tumors that overexpress VLA-4.

Effect of Dopamine D2 Receptor Antagonists on [18F]-FEOBV Binding.

The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D2 receptor antagonists were used to assess changes in [18F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride, or vehicle, 90 min dynamic PET scans were performed with arterial blood sampling. The net influx rate (Ki) was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [18F]-FEOBV concentration in whole-blood or plasma and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted p > 0.07, Cohen's d 0.28-1.89) while the area-under-the-curve (AUC) of the parent fraction of [18F]-FEOBV was significantly higher after haloperidol treatment (adjusted p = 0.022, Cohen's d = 2.51) than in controls. Compared to controls, the AUC of [18F]-FEOBV, normalized for injected dose and body weight, was nonsignificantly increased in the striatum after haloperidol (adjusted p = 0.4, Cohen's d = 1.77) and raclopride (adjusted p = 0.052, Cohen's d = 1.49) treatment, respectively. No changes in the AUC of [18F]-FEOBV were found in the cerebellum (Cohen's d 0.63-0.74). Raclopride treatment nonsignificantly increased Ki in the striatum 1.3-fold compared to control rats (adjusted p = 0.1, Cohen's d = 1.1) while it reduced Ki in the cerebellum by 28% (adjusted p = 0.0004, Cohen's d = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in Ki in the striatum (10%, adjusted p = 1, Cohen's d = 0.44) and a 40-50% lower Ki than controls in all other brain regions (adjusted p < 0.0005, Cohen's d = 3.3-4.7). The changes in Ki induced by the selective D2 receptor antagonist raclopride can in part be quantified using [18F]-FEOBV PET imaging. Haloperidol, a nonselective D2/σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [18F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [18F]-FEOBV to σ receptors using selective σ receptor ligands are necessary.

Fluorine-18-Labeled Fluorescent Dyes for Dual-Mode Molecular Imaging.

Recent progress realized in the development of optical imaging (OPI) probes and devices has made this technique more and more affordable for imaging studies and fluorescence-guided surgery procedures. However, this imaging modality still suffers from a low depth of penetration, thus limiting its use to shallow tissues or endoscopy-based procedures. In contrast, positron emission tomography (PET) presents a high depth of penetration and the resulting signal is less attenuated, allowing for imaging in-depth tissues. Thus, association of these imaging techniques has the potential to push back the limits of each single modality. Recently, several research groups have been involved in the development of radiolabeled fluorophores with the aim of affording dual-mode PET/OPI probes used in preclinical imaging studies of diverse pathological conditions such as cancer, Alzheimer's disease, or cardiovascular diseases. Among all the available PET-active radionuclides, 18F stands out as the most widely used for clinical imaging thanks to its advantageous characteristics (t1/2 = 109.77 min; 97% ß+ emitter). This review focuses on the recent efforts in the synthesis and radiofluorination of fluorescent scaffolds such as 4,4-difluoro-4-bora-diazaindacenes (BODIPYs), cyanines, and xanthene derivatives and their use in preclinical imaging studies using both PET and OPI technologies.

[18F]-SuPAR: A Radiofluorinated Probe for Noninvasive Imaging of DNA Damage-Dependent Poly(ADP-ribose) Polymerase Activity.

Poly(ADP ribose) polymerase (PARP) enzymes generate poly(ADP ribose) post-translational modifications on target proteins for an array of functions centering on DNA and cell stress. PARP isoforms 1 and 2 are critically charged with the surveillance of DNA integrity and are the first line guardians of the genome against DNA breaks. Here we present a novel probe ([18F]-SuPAR) for noninvasive imaging of PARP-1/2 activity using positron emission tomography (PET). [18F]-SuPAR is a radiofluorinated nicotinamide adenine dinucleotide (NAD) analog that can be recognized by PARP-1/2 and incorporated into the long branched polymers of poly(ADP ribose) (PAR). The measurement of PARP-1/2 activity was supported by a reduction of radiotracer uptake in vivo following PARP-1/2 inhibition with talazoparib treatment, a potent PARP inhibitor recently approved by FDA for treatment of breast cancer, as well as ex vivo colocalization of radiotracer analog and poly(ADP ribose). With [18F]-SuPAR, we were able to map the dose- and time-dependent activation of PARP-1/2 following radiation therapy in breast and cervical cancer xenograft mouse models. Tumor response to therapy was determined by [18F]-SuPAR PET within 8 h of administration of a single dose of radiation equivalent to one round of stereotactic ablative radiotherapy.

[18F]GTP1 (Genentech Tau Probe 1), a radioligand for detecting neurofibrillary tangle tau pathology in Alzheimer's disease.

OBJECTIVE: Neurofibrillary tangles (NFTs), consisting of intracellular aggregates of the tau protein, are a pathological hallmark of Alzheimer's disease (AD). Here we report the identification and initial characterization of Genentech Tau Probe 1 ([18F]GTP1), a small-molecule PET probe for imaging tau pathology in AD patients. METHODS: Autoradiography using human brain tissues from AD donors and protein binding panels were used to determine [18F]GTP1 binding characteristics. Stability was evaluated in vitro and in vivo in mice and rhesus monkey. In the clinic, whole-body imaging was performed to assess biodistribution and dosimetry. Dynamic [18F]GTP1 brain imaging and input function measurement were performed on two separate days in 5 ß-amyloid plaque positive (Aß+) AD and 5 ß-amyloid plaque negative (Aß-) cognitive normal (CN) participants. Tracer kinetic modeling was applied and reproducibility was evaluated. SUVR was calculated and compared to [18F]GTP1-specific binding parameters derived from the kinetic modeling. [18F]GTP1 performance in a larger cross-sectional group of 60 Aß+ AD participants and ten (Aß- or Aß+) CN was evaluated with images acquired 60 to 90 min post tracer administration. RESULTS: [18F]GTP1 exhibited high affinity and selectivity for tau pathology with no measurable binding to ß-amyloid plaques or MAO-B in AD tissues, or binding to other tested proteins at an affinity predicted to impede image data interpretation. In human, [18F]GTP1 exhibited favorable dosimetry and brain kinetics, and no evidence of defluorination. [18F]GTP1-specific binding was observed in cortical regions of the brain predicted to contain tau pathology in AD and exhibited low (< 4%) test-retest variability. SUVR measured in the 60 to 90-min interval post injection correlated with tracer-specific binding (slope = 1.36, r2 = 0.98). Furthermore, in a cross-sectional population, the degree of [18F]GTP1-specific binding increased with AD severity and could differentiate diagnostic cohorts. CONCLUSIONS: [18F]GTP1 is a promising PET probe for the study of tau pathology in AD.

Dual-tracer PET/CT scan after injection of combined [18 F]NaF and [18 F]FDG outperforms MRI in the detection of myeloma lesions.

The detection rates of whole-body combined [18 F]NaF/[18 F]FDG positron emission tomography combined with computed tomography (PET/CT), CT alone, whole-body magnetic resonance imaging (WB-MRI), and X-ray were prospectively studied in patients with treatment-requiring plasma cell disorders The detection rates of imaging techniques were compared, and focal lesions were classified according to their anatomic location. Twenty-six out of 30 initially included patients were assessable. The number of focal lesions detected in newly diagnosed patients (n = 13) and in relapsed patients (n = 13) were 296 and 234, respectively. The detection rate of PET/CT was significantly higher than those of WB-MRI (P < 0.05) and CT (P < 0.0001) both in patients with newly diagnosed and in those with relapsed multiple myeloma (MM). The X-ray detection rate was significantly lower than those of all other techniques, while CT detected more lesions compared with WB-MRI at diagnosis (P = 0.025). With regard to the infiltration patters, relapsed patients presented more diffuse patterns, and more focal lesions located in the limbs compared with newly diagnosed patients. In conclusion, the detection rate of [18 F]NaF/[18 F]FDG PET/CT was significantly higher than those of CT, MRI, and X-ray, while the detection rate of X-rays was significantly lower than those of all other imaging techniques except for focal lesions located in the skull.

Preclinical Evaluation of a Fluorine-18 (18F)-Labeled Phosphatidylinositol 3-Kinase Inhibitor for Breast Cancer Imaging.

Breast cancer is one of the commonest malignancies in women, especially in middle-aged and elderly women. Abnormal activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKt/mTOR) pathway has been found to be involved in breast cancer proliferation. Pictilisib (GDC-0941) is a potent inhibitor of PI3K with high affinity and is undergoing phase 2 clinical trials. In this study, we aimed to develop a noninvasive PI3K radiotracer to help determine the mechanism of the PI3K/AKt/mTOR pathway to aid in diagnosis. We designed a new 18F-radiolabeled radiotracer based on the structure of pictilisib, to evaluate noninvasively abnormal activation of the PI3K/AKT/mTOR pathway. To increase the water solubility, and to decrease hepatobiliary and gastrointestinal uptake of the tracer, pictilisib was modified with triethylene glycol di(p-toluenesulfonate) (TsO-PEG3-OTs) to obtain TsO-PEG3-GDC-0941 as the precursor for 18F labeling. A nonradiolabeled reference compound [19F]-PEG3-GDC-0941 was also prepared. Breast cancer cell lines, MCF-7 and MDA-MB-231, were used as high- and low-expression PI3K models, respectively. PET imaging and ex vivo biodistribution assays of [18F]-PEG3-GDC-0941 in MCF-7 and MDA-MB-231 xenografts were also performed, and the results were compared. The precursor compound and reference standard compound were successfully synthesized and identified using NMR and mass spectroscopy. The 18F radiolabeling was achieved with a high yield (61 ± 1%) at a high molar activity (2100 ± 100 MBq/mg). MicroPET images and biodistribution studies showed a higher uptake of the radiotracer in MCF-7 tumors than in MDA-MB-231 tumors (7.56 ± 1.01%ID/g vs 4.07 ± 0.68%ID/g, 1 h postinjection). Additionally, the MCF-7 tumor uptake was significantly decreased when a blocking dose of GDC-0941 was coinjected, indicating high specificity. The liver was found to be the major excretory organ with 5.82 ± 0.88%ID/g at 30 min postinjection for MCF-7 mice. This radiotracer holds great potential for patient screening, diagnosis, and therapy prediction of PI3K-related diseases.

Regulation of Noise-Induced Loss of Serotonin Transporters with Resveratrol in a Rat Model Using 4-[18F]-ADAM/Small-Animal Positron Emission Tomography.

Serotonin (5-HT) plays a crucial role in modulating the afferent fiber discharge rate in the inferior colliculus, auditory cortex, and other nuclei of the ascending auditory system. Resveratrol, a natural polyphenol phytoalexin, can inhibit serotonin transporters (SERT) to increase synaptic 5-HT levels. In this study, we investigated the effects of resveratrol on noise-induced damage in the serotonergic system. Male Sprague-Dawley rats were anaesthetized and exposed to an 8-kHz tone at 116 dB for 3.5 h. Resveratrol (30 mg/kg, intraperitoneal injection [IP]) and citalopram (20 mg/kg, IP), a specific SERT inhibitor used as a positive control, were administered once a day for four consecutive days, with the first treatment occurring 2 days before noise exposure. Auditory brainstem response testing and positron emission tomography (PET) with N,N-dimethyl-2-(2-amino-4-[18F]fluorophenylthio)benzylamine (4-[18F]-ADAM, a specific radioligand for SERT) were used to evaluate functionality of the auditory system and integrity of the serotonergic system, respectively, before and after noise exposure. Finally, immunohistochemistry was performed 1 day after the last PET scan. Our results indicate that noise-induced serotonergic fiber loss occurred in multiple brain regions including the midbrain, thalamus, hypothalamus, striatum, auditory cortex, and frontal cortex. This noise-induced damage to the serotonergic system was ameliorated in response to treatment with resveratrol and citalopram. However, noise exposure increased the hearing threshold in the rats regardless of drug treatment status. We conclude that resveratrol has protective effects against noise-induced loss of SERT.

PET Imaging of 18F-(2 S,4 R)4-Fluoroglutamine Accumulation in Breast Cancer: From Xenografts to Patients.

Sustaining the growth of tumor cells requires extra energy and metabolic building blocks. In addition to consuming glucose, glutamine may play the role as an alternative source of nutrient for growth and survival. We aim to characterize a glutamine analog, 18F-(2 S,4 R)4-fluoroglutamine (18F-(2 S,4 R)4-FGln), as an imaging agent for interrogating the role of glutamine from the in vitro study of tumor cells to clinical manifestation in breast cancer patients. Purity was measured by radio-high-performance liquid chromatography (radio-HPLC), and the stability after production was evaluated in phosphate buffer saline (PBS), saline, and mouse and human serum buffers. The presence of Myc expression in MCF-7 and U87 cells was conducted using qPCR. In vitro cell uptake of 18F-(2 S,4 R)4-FGln in MCF-7 and U87 cells was directly compared with 18F-fluorodeoxyglucose (18F-FDG). In vivo biodistribution and micro-PET imaging of 18F-(2 S,4 R)4-FGln in MCF-7 bearing BALB/c nude mice were performed. PET/CT imaging of 18F-(2 S,4 R)4-FGln was compared with 18F-FDG in the same group of breast cancer patients ( n = 10). We successfully synthesized 18F-(2 S,4 R)4-FGln with a high radiochemical purity (>98%), and the radiochemical purity was unchanged in PBS and saline buffers during a 2 h incubation. In vitro cell uptake studies of 18F-(2 S,4 R)4-FGln displayed a rapid and higher uptake in MCF-7 and U87 cells as compared with 18F-FDG. Biodistribution and micro-PET images showed excellent tumor accumulation of 18F-(2 S,4 R)4-FGln in the MCF-7-implanted mice tumor model. In a preliminary clinical study, 18F-(2 S,4 R)4-FGln/PET detected more lesions in breast cancer patients than 18F-FDG/PET (90% vs 80%). Additionally, in one patient with breast lobular carcinoma, there was a lesion mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax) for 18F-(2 S,4 R)4-FGln higher than those obtained by 18F-FDG, as determined by PET imaging. 18F-(2 S,4 R)4-FGln may be a useful glutamine-targeting metabolic probe for noninvasive imaging of breast cancer.

In Silico, in Vitro, and in Vivo Evaluation of New Candidates for α-Synuclein PET Imaging.

Accumulation of α-synuclein (α-syn) is a neuropathological hallmark of synucleinopathies. To date, no selective α-syn positron emission tomography (PET) radiotracer has been identified. Our objective was to develop the first original, selective, and specific α-syn PET radiotracer. Chemical design inspired from three structural families that demonstrated interesting α-syn binding characteristics was used as a starting point. Bioinformatics modeling of α-syn fibrils was then employed to select the best molecular candidates before their syntheses. An in vitro binding assay was performed to evaluate the affinity of the compounds. Radiotracer specificity and selectivity were assessed by in vitro autoradiography and in vivo PET studies in animal (rodents) models. Finally, gold standard in vitro autoradiography with patients' postmortem tissues was performed to confirm/infirm the α-syn binding characteristics. Two compounds exhibited a good brain availability and bound to α-syn and Aß fibrils in a rat model. In contrast, no signal was observed in a mouse model of synucleinopathy. Experiments in human tissues confirmed these negative results.