Ro in pet what is performance for

Participants included cognitively unimpaired controls, patients with mild cognitive impairment, patients with AD dementia, and with non-AD neurodegenerative disorders. Results Diagnostic groups among the participants included cognitively unimpaired mean [SD] age, Retention of [ 18 F]RO was not pronounced in patients with svPPA, and head-to-head comparison revealed lower temporal lobe uptake than with [ 18 F]flortaucipir.

Tau-selective positron emission tomographic PET tracers have facilitated in vivo studies of tau pathology in neurodegenerative disorders. To our knowledge, there have been no head-to-head comparisons with other imaging or cerebrospinal fluid CSF markers. We also directly compared [ 18 F]RO and [ 18 F]flortaucipir in a subset of patients with svPPA to examine the specificity of both tracers. All participants gave written informed consent; no financial compensation was provided.

The present study was conducted from September 4, , to August 28, To cover brain areas affected by neurofibrillary tangle pathology across the course of AD, 28 , 29 4 FreeSurfer-based composite regions of interest ROIs were created. To examine the [ 18 F]RO signal in regions that are comparatively unaffected by neurofibrillary tangle pathology, 29 primary sensory and motor cortex ROIs were included.

For the head-to-head comparison between [ 18 F]RO and [ 18 F]flortaucipir in svPPA, owing to the focal nature of retention with [ 18 F]flortaucipir in patients with svPPA confined to the anterior temporal lobe, including the white matter , participant-specific ROIs were drawn encompassing voxels showing elevated SUVRs within the temporal lobes, including subcortical white matter eMethods 3 in the Supplement.

Additional details can be found in eMethods 4 in the Supplement. Groups were compared using Kruskal-Wallis or Fisher exact tests. Familywise error—corrected maps are shown in eFigure 4 in the Supplement. All analyses were performed in R, version 3.

Baseline characteristics are provided in Table 1 and in the eResults and eTable 2 in the Supplement. Voxelwise comparisons are shown in Figure 1 C and eFigure 3 in the Supplement. Familywise error—corrected results are shown in eFigure 4 in the Supplement. The diagnostic performance of [ 18 F]RO when separating AD from different types of non-AD disorders was high except when distinguishing AD from dementia with Lewy bodies, where specificity was low Resulting AUC values did not differ significantly from those including all participants eTable 11 in the Supplement.

Tau PET may thus have greater value for differential diagnosis of dementia as opposed to early disease where CSF biomarkers may have better sensitivity. While our findings are consistent with earlier work showing that tau PET outperformed MRI in differentiating AD from non-AD disorders, 9 the present study is, to our knowledge, the first to report findings from a large number of individuals using a second-generation tau tracer and directly compare the diagnostic performance of tau PET, MRI, and CSF markers for AD vs other neurodegenerative disorders.

The optimal diagnostic marker may depend on disease phase. Strengths of this study include the large sample size, the use of a novel tau tracer with image acquisition performed in a single PET center, and the multiple imaging and fluid biomarkers used for comparisons of diagnostic performance.

This study has limitations. One limitation was that clinical diagnosis was considered to be the reference standard, as autopsy data were not available. Because the clinical diagnosis of AD may be inaccurate, 66 the standard used for comparison in the receiver operating characteristic analysis was suboptimal. Furthermore, the number of participants in several of the non-AD subgroups was small eg, multiple system atrophy and vascular dementia.

Findings in these groups should be considered preliminary. Our approach was conservative and consistent with those used in comparable studies. Published Online: May 11, JAMA Neurology. Author Contributions: Dr Leuzy had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Critical revision of the manuscript for important intellectual content: All authors. Dr Klein reported receiving personal fees from F. Hoffmann-La Roche Ltd during the conduct of the study.

Dr Hansson reported receiving grants from Roche during the conduct of the study as well as grants from Roche, nonfinancial support from GE Healthcare, and grants from Biogen outside the submitted work.

No other disclosures were reported. Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy Continue. Download PDF Comment. Figure 1. View Large Download.

Figure 2. Figure 3. The methods to measure the amount of plasma protein binding and the free fraction of radiotracer were discussed in detail by Moein et al [ 25 ]. In , Kazunori Kawamura et al. PBBs, a family of pyridyl and phenyl-butadienyl-benzothiazoles compounds, were initially examined by Makoto Higuchi et al.

It has a large affinity for tau protein aggregates with a K d value of 2. In another study, the group also revealed that [ 11 C] PBB3 readily degraded to form a polar radiometabolite [ 49 , 51 ] and thus potentially impeding a simplified PET image analysis.

A small radioactive metabolite peak [ 11 C]M1 at 0. The mass of the main metabolite [ 11 C]M2 which appears at 1. Adapted with permission from Ref. Only a small variation between mouse and human samples were detected for the radiometabolism of [ 11 C]PBB3 in vitro by cytochrome P and sulfotransferase enzymes.

Therefore, [ 11 C]PBB3 metabolism in mice may offer a substantial understanding of the pharmacokinetic behavior of the radiotracer with PET imaging in humans. These results have established that the radiotracer [ 11 C]PBB3 mostly metabolized to produce [ 11 C]M2 a sulfate conjugation reaction facilitated by sulfotransferases enzymes and a negligible radiometabolite, [ 11 C]M1, was produced due to oxidation being interposed by the CYPs Fig.

Hence, it is extremely important to determine the metabolic pathway and radiometabolite structure for assessing the clinical usage of [ 11 C]PBB3. Besides, the information also could be used in designing new PBB analogs which are more efficient and biostable than the parent compound.

In , Amini et al. According to this strategy, the radiometabolites were first formed in vitro by liver microsomes as radiotracers are mostly metabolized in the liver. The in vivo metabolic profiles are then related to and recognized by the help of the in vitro results. When the in vitro radiometabolism of [ 11 C]flumazenil was analyzed by fast radio-LC, it offered three peaks corresponding to [ 11 C]flumazenil and its two radiometabolites, -[ 11 C]flumazenil-M1 and [ 11 C]flumazenil-M2.

Mass spectrometry analysis offers monoisotopic masses of [ 11 C]flumazenil, its radiometabolites, and their fragmented ions. This result is compared to the one reported previously [ 55 ]. The two radiometabolites of flumazenil were identified—one is a hydroxyl-ethyl ester flumazenil-M1 and the other one is an acid flumazenil-M2. These results demonstrate that the identical fragmentation of flumazenil occurs due to radiometabolism.

To identify the in vivo metabolism of [ 11 C]flumazenil, after administration of the radiotracer, samples from the rhesus monkey plasma were collected at intervals and examined by fast radio-LC Fig.

When the metabolic stability of [ 11 C] flumazenil in vitro no carrier-added as well as in vivo was examined, the radiotracer metabolism rate was found to be faster in in vivo than in in vitro. Nevertheless, both in vitro and in vivo experiments produce an equal number of radiometabolites and in both cases, [ 11 C]flumazenil-M2 appears to be the major radiometabolite.

A similar metabolic profile was reported in primates and human plasma [ 56 , 57 , 58 , 59 ]. There were no metabolites detected in the absence of any microsomes in in vitro. These results demonstrate the microsome dependency of radiometabolite formation of [ 11 C]flumazenil.

The most important metabolite of [ 11 C]flumazenil is an acid, and it does not penetrate the blood—brain barrier in normal human subjects [ 60 ].

Besides, it has negligible in vitro human benzodiazepine receptors binding affinity. Hence, the radioactive metabolite could only marginally impact the estimation of free ligand concentration in the brain and the interpretation of the PET data.

Carrier-added solutions of [ 11 C]PBR28 were incubated with human liver microsomes to find out its phase I radiometabolism [ 54 ]. The metabolism reaction was paused at different intervals and the progress of radiometabolite formation was examined using fast radio-LC. The radiotracer peak and the produced radiometabolite peaks were isolated and recognized by mass spectrometry.

The identity of the radiometabolite was additionally established by matching its retention time with the reference standard of PBRM1. The in vivo metabolite identification was demonstrated by comparing the retention times of its in vitro metabolite peaks. In the case of the in vivo radiometabolism study, after the injection of [ 11 C]PBR28 in a human, the plasma samples were acquired at multiple time intervals and examined with standard radio-LC and fast radio-LC Fig.

The examination of the metabolic stability of the [ 11 C]PBR28 radiotracers confirmed that they are metabolized faster in in vitro than in in vivo. Interestingly enough, four additional radiometabolite peaks were observed when [ 11 C]PBR28 was incubated with the human liver microsome.

However, these peaks are missing in human plasma. Although the above strategy can be successfully applied to identify the chemical form of several radiometabolites, it is quite difficult to foresee the comparative quantity of radiometabolites formed in in vivo with the help of the in vitro route. The radioligands and their identified radiometabolites are marked on each chromatogram. Five major radiometabolites were identified due to the different kinds of in vitro enzymatic biotransformations, including N-dealkylation and benzylic hydroxylation followed by additional oxidation of benzyl alcohol, the primary metabolite.

The study also demonstrates the in vivo radiometabolism by analyzing the plasma samples from a rhesus monkey at different time points after the administration of [ 18 F]FE-PE2I by using conventional radio-LC and fast radio-LC.

Seven different radiometabolite peaks were separated with the help of a fast radio-LC and among them, five were recognized. However, only two radiometabolite peaks were witnessed by the conventional radio-HPLC as reported elsewhere [ 63 , 64 ]. When examining the metabolic stability of [ 18 F]FE-PE2I, it was observed that the rate of radiometabolism is faster in the case of in vitro than in vivo.

Although equal numbers of radioactive metabolites were identified both in in vitro as well as in in vivo analysis, the major radiometabolite amount significantly varies between the two studies. Similar kinds of variations between in vivo and in vitro radiometabolites formed are also observed in other studies [ 65 , 66 ].

Christer et al. The results suggest that the metabolites were produced in in vitro because of the following biotransformation: N-benzylic hydroxylation, S-oxidation, and demethylation Fig. In , Peter Brust et al. The bridgehead nitrogen N 8 hydroxylation N 8 followed by a conjugation reaction by glucuronic acid leads to the formation of a phase II radiometabolite h-M2, which is the same as [ 18 F]M7a, produced in vitro.

Hence, the radioactive metabolites spotted in humans was in decent accordance with those produced by the human liver microsomes Fig. The structures of h-M1 as well as also h-M2 are highly lipophobic and hence have a lesser chance to pass through the blood—brain barrier. In a clinical study, a radiometabolite was noticed in very small amounts by the radio-HPLC, but no characterization study was performed [ 76 ].

Scaling was adjusted for each chromatogram. Improvement of the metabolic stability of the radiotracer is as important as the analysis and identification of its radiometabolites. An increase in metabolic stability could improve the quality of PET imaging results. There are two major ways to improve the metabolic stability of the radiotracer.

The first approach is to substitute the hydrogen present in the reactive site by deuterium. The deuterium substitution of the methyl or ethyl group will usually reduce the rate of metabolism as it requires higher energy to cleave a carbon—deuterium covalent bond other than the carbon—hydrogen bond simply due to a higher mass effect of deuterium. The second approach is to change the labeling position without altering any of the structural or chemical changes of the parent radiotracer.

In this section, we will look into the case study for the above two approaches using [ 18 F]Fluorocholine and [ 11 C]WAY, respectively. Choline radiotracers are commonly applied for clinical PET imaging in oncology [ 79 , 80 ].

In , Smith et al. Chemical oxidation of these radiotracers by the chemical potassium permanganate shows that [ 18 F]fluoro-[1,H4]choline has relatively higher stability to oxidation when compared to [ 18 F]fluorocholine, which was expected from the isotope effect Fig. Radio-HPLC profiles indicate the presence of almost similar amounts of the original radiotracers and the major radiometabolite, betaine for [ 18 F]fluorocholine after incubation with potassium permanganate for 20 min.

However, only a trace amount of betaine was observed for [ 18 F]fluoro-[1,H4]choline in the same conditions. Oxidative stability of these radiotracers was also examined against the enzyme choline oxidase Fig.

However, both enzymatic oxidation and in vitro chemical examination of [ 18 F]fluorocholine and its di-deuterated analog directed that the later have higher oxidative resistance than [ 18 F]fluorocholine.

This in vitro result is also supported by the in vivo radiometabolite profile. The radio-HPLC exploration of plasma samples provided some additional indication for an increase in the resistance of the [ 18 F]fluoro-[1,H4]choline against oxidation relative to the [ 18 F]fluorocholine. In the case of [ 18 F]fluorocholine, simply a little portion of the original radiotracer was detected in the radio-HPLC profile. However, a considerable peak in the original radiotracer was still spotted in the plasma sample for [ 18 F]fluoro-[1,H4]choline.

A biodistribution study in mice with the HCT tumors also confirmed the better in vivo stability and higher uptake of [ 18 F]fluoro-[1,H4]choline in different tissues, including tumor. Importantly, [ 18 F]fluoro-[1,H4]choline shows a considerably higher tumor uptake than [ 18 F]fluorocholine at later time intervals. However, it rapidly cleared from the region that was almost devoid of 5-HT1A receptors such as the cerebellum. Compared to [O-methyl- 11 C]WAY, [carbonyl- 11 C]WAY offers about 10 and 3 times superior signal contrast in receptor-affluent regions of the human and monkey brain, respectively.

In the human plasma, a negligible radiometabolite was detected as [carbonyl- 11 C]desmethyl-WAY but it was almost undetectable in the monkey plasma. In order to identify its effects in PET imaging, [carbonyl- 11 C]cyclohexanecarboxylic acid was administrated into the cynomolgus monkeys and the PET study was then performed. The PET examination concludes that the [ 11 C]cyclohexanecarboxylicacid uptake was extremely low in the brain tissue and that it does not affect the PET study.

Besides, the radiotracer also shows the significant noisy signal at later time point [ 82 ]. In , Magnus et al. These results prove that the defluorination rate of the radiotracer can be minimized by the deuterium isotope effect. However, the application of the 11 C-MePPEP was challenging due to the short half-life of the carbon radioisotope Terry et al. Two other analogs of verapamil, labeled with fluorine, were also reported [ 86 ] [ 18 F]1 and [ 18 F]2, Fig.

However, all these three radiotracers suffer from complicated image interpretation due to their poor metabolic stability [ 86 , 88 ]. Hence, to develop a stable radiotracer for P-gp, Raaphorst et al. They also aimed to evaluate their metabolic pathway. It was discovered that the metabolic stability of [ 18 F]1 and [ 18 F]2 could be enhanced by the addition of deuterium in the parent radiotracer.

They also observed that the deuterium substituted methyl containing analogs [ 18 F]3-d3 and [ 18 F]3-d7 showed better metabolic stability compared to their corresponding unsubstituted analogs.

This increased metabolic stability could be due to enhanced steric hindrance which eventually slows down the enzymatic metabolism. Therefore, [ 18 F]3-d7 could be a potential metabolically stable radiotracer for the clinical evaluation of P-gp. Chemical structures of deuterated nor- verapamil analogs. PET is presently one of the most beneficial imaging tools for measuring drug pharmacokinetics non-invasively in the tissue of interest.

Since the last decade, PET studies have offered a lot of important information regarding the tissue accumulation of numerous types of drugs. The identification of radiometabolites is extremely important as they could offer some important information about the appropriate part of the compound to attach the radioactive label. From the image analysis point of view, detailed knowledge of the radiometabolite formation is required to get the maximum information from a PET scan.

However, the identification of the radiometabolites is quite difficult because of its very short-lived radioisotope and the low dosage of the radiopharmaceutical and its metabolites. The tedious sample preparation procedure makes it even more complicated to analyze the radiometabolite in in vivo. Here, in this review, we have given important information and updates regarding the radiometabolite analysis of several carbon and fluorinebased radiotracers from in vitro, preclinical and clinical aspects.

A positron-emission transaxial tomograph for nuclear imaging PETT. Application of annihilation coincidence detection to transaxial reconstruction tomography. J Nucl Med. PubMed Google Scholar. Brain radioligands--state of the art and new trends. CAS Google Scholar. Phelps ME. PET: the merging of biology and imaging into molecular imaging. Herschman HR. Micro-PET imaging and small animal models of disease.

Curr Opin Immunol. Pike VW. PET radiotracers: crossing the blood—brain barrier and surviving metabolism. Trends Pharmacol Sci. A philosophy for CNS radiotracer design. Acc Chem Res. PET studies with carbon radioligands in neuropsychopharmacological drug development. Curr Pharm Des. Comar D. Analyses of [18F] altanserin bolus injection PET data. II: consideration of radiolabeled metabolites in humans.

Williams RT. Detoxication mechanisms: the metabolism and detoxication of drugs, toxic substances, and other organic compounds: Wiley; Google Scholar. Silverman RB. Petrides GLaPE. Biochemie und Pathobiochemie: Springer; Pharmacokinetic imaging: a noninvasive method for determining drug distribution and action. Clin Pharmacokinet. Radiation oncology: a century of achievements. Nat Rev Cancer. Radiotherapy: what can be achieved by technical improvements in dose delivery? Lancet Oncol. PubMed Article Google Scholar.

Bortfeld T. IMRT: a review and preview. Phys Med Biol. Advances in neuro-oncology imaging. Nat Rev Neurol. Nat Rev Urol. Bentzen SM. Theragnostic imaging for radiation oncology: dose-painting by numbers.

Brahme A, Argren A. Optimal dose distribution for eradication of heterogeneous tumors. Acta Oncol. Molecular imaging of gliomas with PET: opportunities and limitations. Neuro Oncol. Response assessment in Neuro-oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas. Radiother Oncol. Margin reduction in radiotherapy for glioblastoma through 18F-fluoroethyltyrosine PET?

Impact of [18F]-fluoro-ethyl-tyrosine PET imaging on target definition for radiation therapy of high-grade glioma. Nucl Med Biol. Biopsy validation of 18F-DOPA PET and biodistribution in gliomas for neurosurgical planning and radiotherapy target delineation: results of a prospective pilot study. BMC Cancer. J Neuro-Oncol. Clin Adv Hematol Oncol. PubMed Google Scholar. Serial FLT PET imaging to discriminate between true progression and pseudoprogression in patients with newly diagnosed glioblastoma: a long-term follow-up study.

J Nucl Med. TSPO imaging-guided characterization of the immunosuppressive myeloid tumor microenvironment in patients with malignant glioma. The use of dynamic O- F-fluoroethyl -l-tyrosine PET in the diagnosis of patients with progressive and recurrent glioma. Langen K-J, Watts C. Neuro-oncology: amino acid PET for brain tumours—ready for the clinic? Role of O- F-fluoroethyl -L-tyrosine PET for differentiation of local recurrent brain metastasis from radiation necrosis. Google Scholar. Radiat Oncol.

Current status of SSR-directed imaging and therapy in meningioma. Clin Transl Imaging. A look ahead: future directions of SSR-directed imaging and therapy in meningioma. Article Google Scholar. Effect of 11C-methionine-positron emission tomography on gross tumor volume delineation in stereotactic radiotherapy of skull base meningiomas.

No Shinkei Geka. Semin Radiat Oncol. Rev Esp Med Nucl. CAS Google Scholar. Implications of improved diagnostic imaging of small nodal metastases in head and neck cancer: radiotherapy target volume transformation and dose de-escalation. Ann Oncol. Use of PET and other functional imaging to guide target delineation in radiation oncology.

Clin Physiol Funct Imaging. Predictive value of quantitative diffusion-weighted imaging and F-FDG-PET in head and neck squamous cell carcinoma treated by chemo radiotherapy. Eur J Radiol. Clin Nucl Med. Integrating quantitative morphological and intratumoural textural characteristics in FDG-PET for the prediction of prognosis in pharynx squamous cell carcinoma patients. Clin Radiol. Radiomics features of the primary tumor fail to improve prediction of overall survival in large cohorts of CT- and PET-imaged head and neck cancer patients.

PLoS One. Contrast Media Mol Imaging. Predicting hypoxia status using a combination of contrast-enhanced computed tomography and [ 18 F]-Fluorodeoxyglucose positron emission tomography radiomics features. Imaging tumour hypoxia with positron emission tomography. Br J Cancer. Prognostic value of dynamic hypoxia PET in head and neck cancer: results from a planned interim analysis of a randomized phase II hypoxia-image guided dose escalation trial.

Hypoxia imaging with [18F]HX4 PET in squamous cell head and neck cancers: a pilot study for integration into treatment planning. Nucl Med Commun.

Serial [18F]-fluoromisonidazole PET during radiochemotherapy for locally advanced head and neck cancer and its correlation with outcome.

Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer. Head Neck. FDG PET studies during treatment: prediction of therapy outcome in head and neck squamous cell carcinoma. Functional imaging early during chemo radiotherapy for response prediction in head and neck squamous cell carcinoma; a systematic review.

Oral Oncol. Radiat Oncol J. N Engl J Med. Utility of response assessment PET-CT to predict residual disease in neck nodes: a comparison with the histopathology. Auris Nasus Larynx. CA Cancer J Clin. Cancer statistics, Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial.

Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non—small-cell lung cancer: a meta-analysis. Ann Intern Med. Ann Thorac Surg. Eur Radiol. Staging of non—small-cell lung cancer with integrated positron-emission tomography and computed tomography. Pet-ct—based auto-contouring in non—small-cell lung cancer correlates with pathology and reduces interobserver variability in the delineation of the primary tumor and involved nodal volumes.

Positron emission tomography with 18fluorodeoxyglucose in radiation treatment planning for non-small cell lung cancer: a systematic review. J Thorac Oncol. J Clin Oncol. Durvalumab after chemoradiotherapy in stage III non—small-cell lung cancer. Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. Nucl Med Mol Imaging. The efficacy of PET staging for small-cell lung cancer: a systematic review and cost analysis in the Australian setting.

A systematic review. JAMA Oncol. Analysis of primary tumor metabolic volume during chemoradiotherapy in locally advanced non-small cell lung cancer. Strahlenther Onkol. A single-Centre experience. Eur Urol. BJU Int. Nodal Oligorecurrent prostate Cancer: anatomic pattern of possible treatment failure in relation to elective surgical and radiotherapy treatment templates. Pharmaceuticals Basel. Eur Assoc Urol. Radiomic features from PSMA PET for non-invasive intraprostatic tumor discrimination and characterization in patients with intermediate-and high-risk prostate cancer-a comparison study with histology reference.

Surveillance or metastasis-directed therapy for Oligometastatic prostate Cancer recurrence: a prospective, randomized, multicenter phase II trial. Phase 3 trial of Lu-Dotatate for midgut neuroendocrine tumors. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD Prognostic value of SUR in patients with trimodality treatment of locally advanced esophageal carcinoma.

Clin Transl Oncol. J Med Imaging Radiat Oncol. Expert consensus contouring guidelines for intensity modulated radiation therapy in esophageal and Gastroesophageal junction Cancer. Ablative radiation therapy for locally advanced pancreatic cancer: techniques and results.