Positron Emission Tomography Biomarkers Research Articles

Initial evaluation in healthy humans of [18F]DPA-714, a potential PET biomarker for neuroinflammation

The translocator protein 18 kDa (TSPO), although minimally expressed in healthy brain, is up-regulated in pathological conditions, coinciding with microglial activation. It is thereby a suitable in vivo biomarker of neuroinflammation for detection, evaluation and therapeutic monitoring of brain diseases. We aimed to estimate the radiation dosimetry of the positron emission tomography (PET) TSPO radioligand [(18)F]DPA-714, and we evaluated in healthy volunteers its whole-body uptake and cerebral kinetics. Biodistribution data from mice were used for the prediction of radiation dosimetry. In human studies, a 90-min dynamic PET scan was performed in seven healthy volunteers after injection of [(18)F]DPA-714 (245±45 MBq). Arterial and venous samples were collected from two subjects, and two additional subjects were submitted to whole-body acquisition. Regions of interest were defined over cerebral structures to obtain mean time-activity curves and to estimate the distribution volume ratios by Logan graphical analysis, and over peripheral organs to obtain standard uptake values. The effective dose estimated from biodistribution in mice was 17.2 μSv/MBq. Modeling of regional brain and plasma data showed good in vivo stability of [(18)F]DPA-714 in humans, with only 20% of blood metabolites 20 min postinjection (p.i.). Maximum cerebral uptake was observed 5 min p.i., followed by two decreasing phases: a rapid washout (5-30 min) followed by a slower phase for the remainder of PET acquisition. Whole-body images demonstrate high activity in the gallbladder, heart, spleen and kidneys. This initial study in humans shows that [(18)F]DPA-714 is a promising PET radioligand with excellent in vivo stability and biodistribution, and acceptable effective dose estimation. Therefore, [(18)F]DPA-714 could provide a sensitive measure of neuroinflammatory changes in subsequent clinical investigations.

A within‐subject comparison of 6‐[18F]fluoro‐m‐tyrosine and 6‐[18F]fluoro‐L‐dopa in Parkinson's disease

Progression of Parkinson's disease symptoms is imperfectly correlated with positron emission tomography biomarkers for dopamine biosynthetic pathways. The radiopharmaceutical 6-[(18) F]fluoro-m-tyrosine is not a substrate for catechol-O-methyltransferase and therefore has a more favorable uptake-to-background ratio than 6-[(18) F]fluoro-L-dopa. The objective of this study was to evaluate 6-[(18) F]fluoro-m-tyrosine relative to 6-[(18) F]fluoro-L-dopa with partial catechol-O-methyltransferase inhibition as a biomarker for clinical status in Parkinson's disease. Twelve patients with early-stage Parkinson's disease, off medication, underwent Unified Parkinson Disease Rating Scale scoring, brain magnetic resonance imaging, and 3-dimensional dynamic positron emission tomography using equivalent doses of 6-[(18) F]fluoro-m-tyrosine and 6-[(18) F]fluoro-L-dopa with tolcapone, a catechol-O-methyltransferase inhibitor. Images were realigned within subject, after which the tissue-derived uptake rate constant was generated for volumes of interest encompassing the caudate nucleus, putamen, and subregions of the putamen. We computed both bivariate (Pearson) and partial (covariate of age) correlations between clinical subscores and tissue-derived uptake rate constant. Tissue-derived uptake rate constant values were correlated between the radiopharmaceuticals (r = 0.8). Motor subscores were inversely correlated with the contralateral putamen 6-[(18) F]fluoro-m-tyrosine tissue-derived uptake rate constant (|r| > 0.72, P < .005) but not significantly with the 6-[(18) F]fluoro-L-dopa tissue-derived uptake rate constant. The uptake rate constants for both radiopharmaceuticals were also inversely correlated with activities of daily living subscores, but the magnitude of correlation coefficients was greater for 6-[(18) F]fluoro-m-tyrosine. In this design, 6-[(18) F]fluoro-m-tyrosine uptake better reflected clinical status than did 6-[(18) F]fluoro-L-dopa uptake. We attribute this finding to 6-[(18) F]fluoro-m-tyrosine's higher affinity for the target, L-aromatic amino acid decarboxylase, and the absence of other major determinants of the uptake rate constant. These results also imply that L-aromatic amino acid decarboxylase activity is a major determinant of clinical status.

Non-invasive imaging in experimental medicine for drug development

Clinical imaging offers a range of methods for the support of drug development that are able to address major questions related to target validation and molecule biodistribution, target interactions and pharmacodynamics. Here we review recent innovative applications of positron emission tomography (PET) and magnetic resonance imaging (MRI). New approaches to human target validation exploring MRI or PET biomarker changes related to allelic variation at candidate target loci can contribute to human target validation. PET molecular imaging can define molecule biodistribution directly and, if an appropriate, target-specific radioligand is available, be employed in small experimental medicine studies to provide plasma pharmacokinetic-target occupancy data to guide dose selection. An enlarging range of imaging biomarkers for pharmacodynamic studies is enabling imaging experimental medicine studies to assess the potential efficacy of new therapeutic molecules. Integration of these approaches promises improvements in therapeutic molecule differentiation and may contribute in ways that would improve the value proposition for use of a new drug through patient stratification.

In vivo demonstration of amyloid burden in posterior cortical atrophy: a case series with PET and CSF findings

Our objective was to evaluate amyloid deposition in posterior cortical atrophy (PCA), using both cerebrospinal fluid (CSF) biomarker analysis and amyloid imaging. Five PCA patients, selected based on their neuropsychological profile and atrophic changes in posterior regions on MRI, underwent CSF analysis. CSF amyloid-beta 1-42, total tau, and phosphorylated tau at threonine 181 levels were determined. They also had positron emission tomography (PET) with Pittsburgh Compound B ([(11)C]PIB). [(11)C]PIB ratio images were assessed with visual, regional and voxel-based analyses and compared to eight typical Alzheimer's disease (AD) patients and eight controls. The biological profile in the five PCA patients, resulting from CSF and [(11)C]PIB images analysis, was consistent with AD. Individual comparisons of PCA patients' [(11)C]PIB images with the AD group with Statistical Parametric Mapping (SPM) revealed a distinctive posterior uptake in four out of the five patients showing increased amyloid deposition in occipital, temporal, and/or parietal regions. ROI group analysis showed a tendency for higher amyloid deposition in occipital and temporal regions. However, this pattern was not found with SPM group analysis when the global level of [(11)C]PIB uptake was used as a covariate. Our results indicate that amyloid burden can be demonstrated in vivo in PCA suggesting a diagnosis of AD. PCA patients may present a higher global amyloid load than AD that was not related to age at onset, disease severity, disease duration, or educational level in our study. Combined CSF and PET biomarkers seem helpful for in vivo diagnosis of this focal syndrome with underlying AD pathology.

25 Years Full of Chemical Discovery

25 Years Full of Chemical Discovery

The role and future potential of fluorinated biomarkers in positron emission tomography

Importance of the field: Positron emission tomography (PET) is rapidly emerging as the functional imaging method of choice for in vivo imaging applications in a number of key areas of drug discovery and clinical pathology, but especially in oncology. One key limitation of PET is the requirement for rapid synthesis and purification of biomarker/drug molecules regiospecifically labelled with short-lived positron-emitting isotopes.Areas covered in this review: In this review, we focus on the role of 18F-labelled molecules in PET, presenting a perspective on the challenges associated with the synthesis and future clinical utility of a range of labelled small molecules and macromolecular structures. Further preclinical method development for the regiospecific synthesis of fluorinated biomarkers under mild conditions is required before a wide range of 18F-labelled molecules take their place alongside clinically established oncology biomarkers such as 18FDG and 18FLT.What the reader will gain: In this review, we offer insights into current and future chemical methods for the efficient synthesis of fluorinated PET biomarkers, featuring modern technologies such as microwave-promoted chemistries and microfluidic reactors, both of which possess the capability to routinely and rapidly produce the small quantities of PET-labelled molecules under the mild and efficient conditions that are required for PET tracer synthesis.Take home message: 18F PET is a flourishing field with many applications in drug discovery and development, through radiolabelling of drug molecules or use of fluorinated disease biomarkers.

11C]-dimethylamine as a labeling agent for PET biomarkers

The dimethylamine functional group is a common component of the chemical structure of numerous drugs. The most commonly used synthetic route for carbon-11 labeled radiopharmaceuticals which contain the dimethylamine group is via C-11 methylation of the monomethyl amine precursors. Here we describe the radiosynthesis of [ 11C]dimethylamine ( 1) and its application in the direct labeling of several positron emission tomography (PET) imaging agents by-passing the preparation of the monomethyl amine precursors.

In Vivo Molecular Imaging Biomarkers: Clinical Pharmacology’s new “PET”?

Medicine, including the pharmaceutical and biotechnology industries as well as many clinical practitioners, has recognized the importance of using molecular imaging biomarkers, including those labeled in such a way as to be imaged by positron emission tomography (PET), as tools for predicting outcomes in drug development and creating opportunities for "personalized" medicine, for diagnosing early-stage disease, and for the follow-up of the effectiveness of treatment.(1) However, only one important and widely used PET biomarker is currently approved by the Food and Drug Administration (FDA). If the technology is so important, we can ask why there is such a limitation to the availability of these biomarkers.

11C]Choline as a PET biomarker for assessment of prostate cancer tumor models

[ 11C]Choline has been evaluated as a positron emission tomography (PET) biomarker for assessment of established human prostate cancer tumor models. [ 11C]Choline was prepared by the reaction of [ 11C]methyl triflate with 2-dimethylaminoethanol (DMAE) and isolated and purified by solid-phase extraction (SPE) method in 60–85% yield based on [ 11C]CO 2, 15–20 min overall synthesis time from end of bombardment (EOB), 95–99% radiochemical purity and specific activity >0.8 Ci/μmol at end of synthesis (EOS). The biodistribution of [ 11C]choline was determined at 30 min post iv injection in prostate cancer tumor models C4-2, PC-3, CWR22rv, and LNCaP tumor-bearing athymic mice. The results showed the accumulation of [ 11C]choline in these tumors was 1.0% dose/g in C4-2 mouse, 0.4% dose/g in PC-3 mice, 3.2% dose/g in CWR22rv mice, and 1.4% dose/g in LNCaP mice; the ratios of tumor/muscle (T/M) and tumor/blood (T/B) were 2.3 (T/M, C4-2), 1.4 (T/M, PC-3), 2.5 (T/M, CWR22rv), 1.2 (T/M, LNCaP) and 2.6 (T/B, C4-2), 2.6 (T/B, PC-3), 7.8 (T/B, CWR22rv), 3.2 (T/B, LNCaP), respectively. The micro-PET imaging of [ 11C]choline in prostate cancer tumor models was acquired from a C4-2, PC-3, CWR22rv, or LNCaP implanted mouse at 30 min post iv injection of 1 mCi of the tracer using a dedicated high resolution (<3 mm full-width at half-maximum) small FOV (field-of-view) PET imaging system, IndyPET-II scanner, developed in our laboratory, which showed the accumulation of [ 11C]choline in C4-2, PC-3, CWR22rv, or LNCaP tumor implanted in a nude athymic mouse. The initial dynamic micro-PET imaging data indicated the average T/M ratios were approximately 3.0 (C4-2), 2.1 (PC-3), 3.5 (CWR22rv), and 3.3 (LNCaP), respectively, which showed the tumor accumulation of [ 11C]choline in all four tumor models is high. These results suggest that there are significant differences in [ 11C]choline accumulation between these different tumor types, and these differences might offer some useful measure of tumor biological process.

Radiosynthesis of ML03, a novel positron emission tomography biomarker for targeting epidermal growth factor receptor via the labeling synthon: [ 11C]acryloyl chloride

An automated procedure for the radiosynthesis of the labeling synthon [ 11C]acryloyl chloride was developed and applied for labeling several N-acryl amides with carbon-11. [ 11C]-6-acrylamido-4-(3,4-dichloro-6-fluoroanilino)quinazoline (ML03), a novel PET biomarker targeting the epidermal growth factor receptor tyrosine kinase (EGFr-TK) in cancer, was successfully prepared using this labeled synthon in a fully automated manner. Two other potential anticancer drugs were also labeled using the developed methodology. The potency of ML03 to inhibit autophosphorylation of EGFr-TK was evaluated by an ELISA assay indicating a low IC 50 of 0.037 nM.