Publications
469 results found
Plisson C, Salinas C, Weinzimmer D, et al., 2013, Radiosynthesis and <i>in vivo</i> evaluation in the pig and baboon of candidate phosphodiesterase 10A PET radioligands. Comparison with [<SUP>11</SUP>C]MP-10., Publisher: WILEY-BLACKWELL, Pages: S301-S301, ISSN: 0362-4803
Salinas C, Weinzimmer D, Searle G, et al., 2013, Kinetic analysis of drug-target interactions with PET for characterization of pharmacological hysteresis, JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, Vol: 33, Pages: 700-707, ISSN: 0271-678X
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- Citations: 11
Gudas J, Olafsen T, Ho D, et al., 2013, Evaluation of two engineered antibody fragments derived from a human CD20 antibody as tracers for immunoPET, 104th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Kalk NJ, Guo Q, Cherian R, et al., 2013, Using positron emission tomography to investigate microglial activation in alcohol dependence: preliminary findings, EUROPEAN NEUROPSYCHOPHARMACOLOGY, Vol: 23, Pages: S87-S88, ISSN: 0924-977X
Slifstein M, Rabiner EA, Gunn RN, 2013, Imaging the Dopamine D<inf>3</inf> Receptor In Vivo, Imaging of the Human Brain in Health and Disease, Pages: 265-287, ISBN: 9780124186774
The dopamine D3 receptor has been recognized as a distinct entity from the molecularly similar dopamine D2 receptor, functionally and in anatomical distribution, since 1990, but has not been amenable to characterization of its in vivo properties with imaging techniques for most of that time due to the absence of selective radiotracers. The positron emission tomography radiotracer [11C]-(+)-PHNO, originally developed in 2005 for its D2/D3 agonist properties, has recently been shown to be a strongly D3-preferring tracer that nonetheless binds nontrivially to D2 receptors as well. While the selectivity properties of this tracer present methodological challenges for pharmacokinetic quantification, [11C]-(+)-PHNO imaging has, for the first time, made D3 receptor imaging in the living human brain possible, and several interesting results in neuropsychiatric populations have already begun to emerge. In this chapter, we review the methodological developments of D3 receptor imaging with [11C]-(+)-PHNO in both preclinical species and humans, as well as imaging studies that have been performed in patient populations. © 2014 Elsevier Inc. All rights reserved.
Cox K, Gunn R, 2013, Seeing is believing, Biologist, Vol: 60, Pages: 32-35, ISSN: 0006-3347
Owen D, Guo Q, Colasanti A, et al., 2013, Determination of [11C]PBR28 binding potential in vivo: A first human TSPO occupancy study.
Jiao J, Schnabel JA, Gunn RN, 2013, A Generalised Spatio-Temporal Registration Framework for Dynamic PET Data: Application to Neuroreceptor Imaging, MEDICAL IMAGE COMPUTING AND COMPUTER-ASSISTED INTERVENTION (MICCAI 2013), PT I, Vol: 8149, Pages: 211-218, ISSN: 0302-9743
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- Citations: 2
Tziortzi AC, Haber SN, Searle GE, et al., 2013, Connectivity-Based Functional Analysis of Dopamine Release in the Striatum Using Diffusion-Weighted MRI and Positron Emission Tomography, Cereb Cortex, ISSN: 1460-2199
The striatum acts in conjunction with the cortex to control and execute functions that are impaired by abnormal dopamine neurotransmission in disorders such as Parkinson's and schizophrenia. To date, in vivo quantification of striatal dopamine has been restricted to structure-based striatal subdivisions. Here, we present a multimodal imaging approach that quantifies the endogenous dopamine release following the administration of d-amphetamine in the functional subdivisions of the striatum of healthy humans with [(11)C]PHNO and [(11)C]Raclopride positron emission tomography ligands. Using connectivity-based (CB) parcellation, we subdivided the striatum into functional subregions based on striato-cortical anatomical connectivity information derived from diffusion magnetic resonance imaging (MRI) and probabilistic tractography. Our parcellation showed that the functional organization of the striatum was spatially coherent across individuals, congruent with primate data and previous diffusion MRI studies, with distinctive and overlapping networks. d-amphetamine induced the highest dopamine release in the limbic followed by the sensory, motor, and executive areas. The data suggest that the relative regional proportions of D2-like receptors are unlikely to be responsible for this regional dopamine release pattern. Notably, the homogeneity of dopamine release was significantly higher within the CB functional subdivisions in comparison with the structural subdivisions. These results support an association between local levels of dopamine release and cortical connectivity fingerprints.
Jiao J, Searle GE, Tziortzi AC, et al., 2012, Spatial-temporal pharmacokinetic model based registration of 4D brain PET data, Pages: 100-112, ISSN: 0302-9743
In dynamic positron emission tomography (PET), where scan durations often exceed 1 hour, registration of motion-corrupted dynamic PET images is necessary in order to maintain the integrity of the physiological/pharmacological/ biochemical information derived from the tracer kinetic analysis of the scan. A pharmacokinetic model, which is traditionally used to analyse PET data following any registration, was incorporated into the registration process itself in order to allow for a groupwise registration of the temporal time frames. The new method achieved smaller registration errors and improved kinetic parameter estimates on validation data sets as compared with the traditional image based similarity registration approach. When applied to measured clinical data from 10 healthy subjects scanned with [ 11C]-(+)-PHNO (a dopamine D3/D2 receptor tracer), it reduced the intra-class variability on the tracer kinetics, suggesting a successful registration. Our new method which incorporates a generic tracer kinetic model could be applied widely to dynamic PET data as part of an automated tool to remove motion artefacts and increase the integrity and statistical power of these data. © 2012 Springer-Verlag.
Gunn RN, Jenkinson M, Rabinner EA, et al., 2012, Quantification of dopamine release within the connectivity-derived functional subdivision of striatum, 9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM), Publisher: NATURE PUBLISHING GROUP, Pages: S166-S166, ISSN: 0271-678X
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- Citations: 1
Searle G, Salinas C, Gunn R, 2012, A molecular imaging analysis pipeline aimed at maximising quality and throughput, 9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM), Publisher: NATURE PUBLISHING GROUP, Pages: S160-S161, ISSN: 0271-678X
Veronese M, Zamuner S, Gunn RN, et al., 2012, Optimal design in PET occupancy studies: a sensitivity study, 9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM), Publisher: NATURE PUBLISHING GROUP, Pages: S168-S169, ISSN: 0271-678X
Colasanti A, Guo Q, Onega M, et al., 2012, [<SUP>18</SUP>F]PBR111 binding in multiple sclerosis: relationship to age and clinical variables, 9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM), Publisher: NATURE PUBLISHING GROUP, Pages: S22-S22, ISSN: 0271-678X
Erritzoe D, Tziortzi A, Bargiela D, et al., 2012, <i>In vivo</i> imaging of dopamine D3 receptors in alcoholism using [<SUP>11</SUP>C]PHNO-PET, and a selective D3 receptor antagonist, 9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM), Publisher: SAGE PUBLICATIONS INC, Pages: S77-S78, ISSN: 0271-678X
Guo Q, Colasanti A, Onega M, et al., 2012, Quantification of <SUP>18</SUP>F-PBR111 PET for TSPO imaging in humans, 9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM), Publisher: NATURE PUBLISHING GROUP, Pages: S185-S186, ISSN: 0271-678X
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- Citations: 1
Jones T, Rabiner EA, 2012, The development, past achievements, and future directions of brain PET, JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, Vol: 32, Pages: 1426-1454, ISSN: 0271-678X
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- Citations: 83
Salinas C, Searle G, Gunn R, 2012, A quantitative molecular imaging analysis pipeline for PET oncology studies, Publisher: SOC NUCLEAR MEDICINE INC, ISSN: 0161-5505
Shotbolt P, Tziortzi AC, Searle GE, et al., 2012, Within-subject comparison of [(11)C]-(+)-PHNO and [(11)C]raclopride sensitivity to acute amphetamine challenge in healthy humans, J Cereb Blood Flow Metab, Vol: 32, Pages: 127-136, ISSN: 1559-7016
[(11)C]PHNO is a D(2)/D(3) agonist positron emission tomography radiotracer, with higher in vivo affinity for D(3) than for D(2) receptors. As [(11)C]-(+)-PHNO is an agonist, its in vivo binding is expected to be more affected by acute fluctuations in synaptic dopamine than that of antagonist radiotracers such as [(11)C]raclopride. In this study, the authors compared the effects of an oral dose of the dopamine releaser amphetamine (0.3 mg/kg) on in vivo binding of [(11)C]-(+)-PHNO and [(11)C]raclopride in healthy subjects, using a within-subjects, counterbalanced, open-label design. In the dorsal striatum, where the density of D(3) receptors is negligible and both tracers predominantly bind to D(2) receptors, the reduction of [(11)C]-(+)-PHNO binding potential (BP(ND)) was 1.5 times larger than that of [(11)C]raclopride. The gain in sensitivity associated with the agonist [(11)C]-(+)-PHNO implies that approximately 65% of D(2) receptors are in the high-affinity state in vivo. In extrastriatal regions, where [(11)C]-(+)-PHNO predominantly binds to D(3) receptors, the amphetamine effect on [(11)C]-(+)-PHNO BP(ND) was even larger, consistent with the higher affinity of dopamine for D(3). This study indicates that [(11)C]-(+)-PHNO is superior to [(11)C]raclopride for studying acute fluctuations in synaptic dopamine in the human striatum. [(11)C]-(+)-PHNO also enables measurement of synaptic dopamine in D(3) regions.
Owen DR, Yeo AJ, Gunn RN, et al., 2012, An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28, J Cereb Blood Flow Metab, Vol: 32, Pages: 1-5, ISSN: 1559-7016
[(11)C]PBR28 binds the 18-kDa Translocator Protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of signal are confounded by large interindividual variability in binding affinity, which displays a trimodal distribution compatible with a codominant genetic trait. Here, we tested directly for an underlying genetic mechanism to explain this. Binding affinity of PBR28 was measured in platelets isolated from 41 human subjects and tested for association with polymorphisms in TSPO and genes encoding other proteins in the TSPO complex. Complete agreement was observed between the TSPO Ala147Thr genotype and PBR28 binding affinity phenotype (P value=3.1 x 10(-13)). The TSPO Ala147Thr polymorphism predicts PBR28 binding affinity in human platelets. As all second-generation TSPO PET radioligands tested hitherto display a trimodal distribution in binding affinity analogous to PBR28, testing for this polymorphism may allow quantitative interpretation of TSPO PET studies with these radioligands.
Searle GE, Beaver JD, Tziortzi A, et al., 2012, Mathematical modelling of [(11)C]-(+)-PHNO human competition studies, Neuroimage, Vol: 68C, Pages: 119-132, ISSN: 1095-9572
The D(2)/D(3) agonist radioligand [(11)C]-(+)-PHNO is currently the most suitable D(3) imaging agent available, despite its limited selectivity for the D(3) over the D(2). Given the collocation of D(2) and D(3) receptors, and generally higher densities of D(2), the separation of D(2) and D(3) information from [(11)C]-(+)-PHNO PET data are somewhat complex. This complexity is compounded by recent data suggesting that [(11)C]-(+)-PHNO PET scans might be routinely performed in non-tracer conditions (with respect to D(3) receptors), and that the cerebellum (used as a reference region) might manifest some displaceable binding signal. Here we present the modelling and analysis of data from two human studies which employed an adequate dose range of selective D(3) antagonists (GSK598809 and GSK618334) to interrogate the [(11)C]-(+)-PHNO PET signal. Models describing the changes observed in the PET volume of distribution (V(T)) and binding potential (BP(ND)) were used to identify and quantify a [(11)C]-(+)-PHNO mass dose effect at the D(3), and displaceable signal in the cerebellum, as well as providing refined estimates of regional D(3) fractions of [(11)C]-(+)-PHNO BP(ND). The dose of (+)-PHNO required to occupy half of the available D(3) receptors (ED(50)(PHNO,D3)) was estimated as 40ng/kg, and the cerebellum BP(ND) was estimated as 0.40. These findings confirm that [(11)C]-(+)-PHNO human PET studies are in fact routinely performed under non-tracer conditions. This suggests that (+)-PHNO injection masses should be minimised and tightly controlled in order to mitigate the mass dose effect. The specific binding detected in the cerebellum was modest but could have a significant effect, for example on estimates of D(3) potency in drug occupancy studies. A range of methods for the analysis of future [(11)C]-(+)-PHNO data, incorporating models for the effects quantified here, were developed and evaluated. The comparisons and conclusions drawn from these can inform the design an
Veronese M, Gunn RN, Zamuner S, et al., 2012, A non-linear mixed effect modelling approach for metabolite correction of the arterial input function in PET studies, Neuroimage, Vol: 66C, Pages: 611-622, ISSN: 1095-9572
Quantitative PET studies with arterial blood sampling usually require the correction of the measured total plasma activity for the presence of metabolites. In particular, if labelled metabolites are found in the plasma in significant amounts their presence has to be accounted for, because it is the concentration of the parent tracer which is required for data quantification. This is achieved by fitting a Parent Plasma fraction (PPf) model to discrete metabolite measurements. The commonly used method is based on an individual approach, i.e. for each subject the PPf model parameters are estimated from its own metabolite samples, which are, in general, sparse and noisy. This fact can compromise the quality of the reconstructed arterial input functions, and, consequently, affect the quantification of tissue kinetic parameters. In this study, we proposed a Non-Linear Mixed Effect Modelling (NLMEM) approach to describe metabolite kinetics. Since NLMEM has been developed to provide robust parameter estimates in the case of sparse and/or noisy data, it has the potential to be a reliable method for plasma metabolite correction. Three different PET datasets were considered: [11C]-(+)-PHNO (54 scans), [11C]-PIB (22 scans) and [11C]-DASB (30 scans). For each tracer both simulated and measured data were considered and NLMEM performance was compared with that provided by individual analysis. Results showed that NLMEM provided improved estimates of the plasma parent input function over the individual approach when the metabolite data were sparse or contained outliers.
Gunn R, 2012, COMBINING PET AND EQUILIBRIUM DIALYSIS TECHNOLOGIES FOR THE QUANTITATIVE ASSESSMENT OF CNS PENETRATION, 18th North American Regional International-Society-for-the-Study-of-Xenobiotics (ISSX) Meeting, Publisher: INFORMA HEALTHCARE, Pages: 9-10, ISSN: 0360-2532
Cole DM, Beckmann CF, Searle GE, et al., 2012, Orbitofrontal connectivity with resting-state networks is associated with midbrain dopamine D3 receptor availability, Cereb Cortex, Vol: 22, Pages: 2784-2793, ISSN: 1460-2199
Animal research and human postmortem evidence highlight the importance of brain dopamine D3 receptor (D3R) function in multiple neuropsychiatric disorders, including addiction. Separate anatomical and functional neuroimaging findings implicate disrupted frontal cortical connectivity with distributed brain networks in processes relevant for these diseases. This potential conjunction between molecular and functional markers has not, however, been tested directly. Here, we used a novel combination of [(11)C]-(+)-PHNO positron emission tomography and resting-state functional magnetic resonance imaging in the same healthy individuals to investigate whether differences in midbrain D3R availability are associated with functional interactions between large-scale networks and regions involved in reward processing and cognition. High midbrain D3R availability was associated with reduced functional connectivity between orbitofrontal cortex (OFC) and networks implicated in cognitive control and salience processing. The opposite pattern was observed in subcortical reward circuitry and the "default mode" network, which showed greater connectivity with OFC in individuals with high D3R availability. These findings demonstrate that differential interactions between OFC and networks implicated in cognitive control and reward are associated with midbrain D3R availability, consistent with the hypothesis that dopamine D3R signaling is an important molecular pathway underlying goal-directed behavior.
Jiao J, Salinas CA, Searle GE, et al., 2012, Joint Estimation of Subject Motion and Tracer Kinetic Parameters of Dynamic PET Data in an EM Framework, Conference on Medical Imaging - Image Processing, Publisher: SPIE-INT SOC OPTICAL ENGINEERING, ISSN: 0277-786X
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- Citations: 1
Gallezot JD, Beaver JD, Gunn RN, et al., 2012, Affinity and selectivity of [(1)(1)C]-(+)-PHNO for the D3 and D2 receptors in the rhesus monkey brain in vivo, Synapse, Vol: 66, Pages: 489-500, ISSN: 1098-2396
Although [(1)(1)C]-(+)-PHNO has enabled quantification of the dopamine-D3 receptor (D3R) in the human brain in vivo, its selectivity for the D3R is not sufficiently high to allow us to disregard its binding to the dopamine-D2 receptor (D2R). We quantified the affinity of [(1)(1)C]-(+)-PHNO for the D2R and D3R in the living primate brain. Two rhesus monkeys were examined on four occasions each, with [(1)(1)C]-(+)-PHNO administered in a bolus + infusion paradigm. Varying doses of unlabeled (+)-PHNO were coadministered on each occasion (total doses ranging from 0.09 to 5.61 mug kg(-)(1)). The regional binding potential (BP(ND) ) and the corresponding doses of injected (+)-PHNO were used as inputs in a model that quantified the affinity of (+)-PHNO for the D2R and D3R, as well as the regional fractions of the [(1)(1)C]-(+)-PHNO signal attributable to D3R binding. (+)-PHNO in vivo affinity for the D3R (K(d)/f(ND) ~0.23-0.56 nM) was 25- to 48-fold higher than that for the D2R (K(d)/f(ND) ~11-14 nM). The tracer limits for (+)-PHNO (dose associated with D3R occupancy ~10%) were estimated at ~0.02-0.04 mug kg(-)(1) injected mass for anesthetized primate and at 0.01-0.02 mug kg(-)(1) for awake human positron emission tomography (PET) studies. Our data enabled a rational design and interpretation of future PET studies with [(1)(1)C]-(+)-PHNO.
Parker CA, Gunn RN, Rabiner EA, et al., 2012, Radiosynthesis and characterization of 11C-GSK215083 as a PET radioligand for the 5-HT6 receptor, J Nucl Med, Vol: 53, Pages: 295-303, ISSN: 1535-5667
The development of a PET radioligand for imaging 5-hydroxytryptamine (5-HT) 6 receptors in the brain would, for the first time, enable in vivo imaging of this target along with assessment of its involvement in disease pathophysiology. In addition, such a tool would assist in the development of novel drugs targeting the 5-HT6 receptor. METHODS: On the basis of in vitro data, GSK215083 was identified as a promising 5-HT6 radioligand candidate and was radiolabeled with (11)C via methylation. The in vivo properties of (11)C-GSK215083 were evaluated first in pigs (to investigate brain penetration and specific binding), second in nonhuman primates (to confirm brain penetration, specific binding, selectivity, and kinetics), and third in human subjects (to confirm brain penetration and biodistribution). RESULTS: (11)C-GSK215083 readily entered the brain in all 3 species, leading to a heterogeneous distribution (striatum > cortex > cerebellum) consistent with reported 5-HT6 receptor densities and distribution determined by tissue-section autoradiography in preclinical species and humans. In vivo saturation studies using escalating doses of GSK215083 in primates demonstrated saturable, dose-dependent binding to the 5-HT6 receptor in the striatum. Importantly, (11)C-GSK215083 also exhibited affinity for the 5-HT2A receptor; however, given the differential localization of these 2 receptors in the central nervous system, the discrete 5-HT6 binding properties of this radioligand were able to be determined. CONCLUSION: These data demonstrate the utility of (11)C-GSK215083 as a promising PET radioligand for probing the 5-HT6 receptor in vivo in both preclinical and clinical species.
Gunn RN, Summerfield SG, Salinas CA, et al., 2012, Combining PET biodistribution and equilibrium dialysis assays to assess the free brain concentration and BBB transport of CNS drugs, J Cereb Blood Flow Metab, Vol: 32, Pages: 874-883, ISSN: 1559-7016
The passage of drugs in and out of the brain is controlled by the blood-brain barrier (BBB), typically, using either passive diffusion across a concentration gradient or active transport via a protein carrier. In-vitro and preclinical measurements of BBB penetration do not always accurately predict the in-vivo situation in humans. Thus, the ability to assay the concentration of novel drug candidates in the human brain in vivo provides valuable information for de-risking of candidate molecules early in drug development. Here, positron emission tomography (PET) measurements are combined with in-vitro equilibrium dialysis assays to enable assessment of transport and estimation of the free brain concentration in vivo. The PET and equilibrium dialysis data were obtained for 36 compounds in the pig. Predicted P-glycoprotein (P-gp) status of the compounds was consistent with the PET/equilibrium dialysis results. In particular, Loperamide, a well-known P-gp substrate, exhibited a significant concentration gradient consistent with active efflux and after inhibition of the P-gp process the gradient was removed. The ability to measure the free brain concentration and assess transport of novel compounds in the human brain with combined PET and equilibrium dialysis assays can be a useful tool in central nervous system (CNS) drug development.
Guo Q, Owen DR, Rabiner EA, et al., 2012, Identifying improved TSPO PET imaging probes through biomathematics: the impact of multiple TSPO binding sites in vivo, Neuroimage, Vol: 60, Pages: 902-910, ISSN: 1095-9572
To date, (1)(1)C-(R)-PK11195 has been the most widely used TSPO PET imaging probe, although it suffers from high non-specific binding and low signal to noise. A significant number of 2nd generation TSPO radioligands have been developed with higher affinity and/or lower non-specific binding, however there is substantial inter-subject variation in their affinity for the TSPO. TSPO from human tissue samples binds 2nd generation TSPO radioligands with either high affinity (high affinity binders, HABs), or low affinity (LABs) or expresses both HAB and LAB binding sites (mixed affinity binders, MABs). The expression of these different TSPO binding sites in human is encoded by the rs6971 polymorphism in the TSPO gene. Here, we use a predictive biomathematical model to estimate the in vivo performances of three of these 2nd generation radioligands ((1)(8)F-PBR111, (1)(1)C-PBR28, (1)(1)C-DPA713) and (1)(1)C-(R)-PK11195 in humans. The biomathematical model only relies on in silico, in vitro and genetic data (polymorphism frequencies in different ethnic groups) to predict the radioactivity time course in vivo. In particular, we provide estimates of the performances of these ligands in within-subject (e.g. longitudinal studies) and between-subject (e.g. disease characterisation) PET studies, with and without knowledge of the TSPO binding class. This enables an assessment of the different radioligands prior to radiolabelling or acquisition of any in vivo data. The within-subject performance was characterised in terms of the reproducibility of the in vivo binding potential (%COV[BP(ND)]) for each separate TSPO binding class in normal and diseased states (50% to 400% increase in TSPO density), whilst the between-subject performance was characterised in terms of the number of subjects required to distinguish between different populations. The results indicated that the within-subject variability for (1)(8)F-PBR111, (1)(1)C-PBR28 and (1)(1)C-DPA713 (0.9% to 2.2%) was significantly l
Matthews PM, Rabiner EA, Passchier J, et al., 2012, Positron emission tomography molecular imaging for drug development, Br J Clin Pharmacol, Vol: 73, Pages: 175-186, ISSN: 1365-2125
Human in vivo molecular imaging with positron emission tomography (PET) enables a new kind of 'precision pharmacology', able to address questions central to drug development. Biodistribution studies with drug molecules carrying positron-emitting radioisotopes can test whether a new chemical entity reaches a target tissue compartment (such as the brain) in sufficient amounts to be pharmacologically active. Competition studies, using a radioligand that binds to the target of therapeutic interest with adequate specificity, enable direct assessment of the relationship between drug plasma concentration and target occupancy. Tailored radiotracers can be used to measure relative rates of biological processes, while radioligands specific for tissue markers expected to change with treatment can provide specific pharmacodynamic information. Integrated application of PET and magnetic resonance imaging (MRI) methods allows molecular interactions to be related directly to anatomical or physiological changes in a tissue. Applications of imaging in early drug development can suggest approaches to patient stratification for a personalized medicine able to deliver higher value from a drug after approval. Although imaging experimental medicine adds complexity to early drug development and costs per patient are high, appropriate use can increase returns on R and D investment by improving early decision making to reduce new drug attrition in later stages. We urge that the potential value of a translational molecular imaging strategy be considered routinely and at the earliest stages of new drug development.
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