Kinetic modelling of [<Superscript>11</Superscript>C]flumazenil using data-driven methods

Purpose  [¹¹C]Flumazenil (FMZ) is a benzodiazepine receptor antagonist that binds reversibly to central-type gamma-aminobutyric acid (GABA-A) sites. A validated approach for analysis of [¹¹C]FMZ is the invasive one-tissue (1T) compartmental model. However, it would be advantageous to analyse FMZ binding with whole-brain pixel-based methods that do not require a-priori hypotheses regarding preselected regions. Therefore, in this study we compared invasive and noninvasive data-driven methods (Logan graphical analysis, LGA; multilinear reference tissue model, MRTM2; spectral analysis, SA; basis pursuit denoising, BPD) with the 1T model. Methods  We focused on two aspects: (1) replacing the arterial input function analyses with a reference tissue method using the pons as the reference tissue, and (2) shortening the scan protocol from 90 min to 60 min. Dynamic PET scans were conducted in seven healthy volunteers with arterial blood sampling. Distribution volume ratios (DVRs) were selected as the common outcome measure. Results  The SA, LGA with and without arterial input, and MRTM2 agreed best with the 1T model DVR values. The invasive and noninvasive BPD were slightly less well correlated. The full protocol of a 90-min emission data performed better than the 60-min protocol, but the 60-min protocol still delivered useful data, as assessed by the coefficient of variation, and the correlation and bias analyses. Conclusion  This study showed that the SA, LGA and MRTM2 are valid methods for the quantification of benzodiazepine receptor binding with [¹¹C]FMZ using an invasive or noninvasive protocol, and therefore have the potential to reduce the invasiveness of the procedure.     

Potential of an adenosine A<Subscript>2A</Subscript> receptor antagonist [<Superscript>11</Superscript>C]TMSX for myocardial imaging by positron emission tomography: a first human study

In previous in vivo studies with mice, rats, cats and monkeys, we have demonstrated that [7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)- 1,3,7-trimethylxanthine ([11C]TMSX) is a potential radioligand for mapping adenosine A2A receptors of the brain by positron emission tomography (PET). In the present study, we studied the potential of [11C]TMSX for myocardial imaging. Uptake of radioactivity by the heart was high and gradually decreased after an intravenous injection of [11C]TMSX into mice. In metabolite analysis, 54% and 76% of the radioactivity in plasma and heart, respectively, were present as the unchanged form of [11C]TMSX 60 min postinjection. The myocardial uptake was reduced by carrier-loading and by co-injection of an adenosine A2A antagonist CSC, but not by co-injection of an adenosine A1 antagonist DPCPX. Pretreatment with a high dose of a non-selective antagonist theophylline also reduced the myocardial uptake of [11C]TMSX. These findings demonstrate the specific binding of [11C]TMSX to adenosine A2A receptors in the heart. Finally we successfully performed the myocardial imaging by PET with [11C]TMSX in a normal volunteer. A graphical analysis by Logan plot supported the receptor-mediated uptake of [11C]TMSX. Peripherally [11C]TMSX was very stable in human: >90% of the radioactivity in plasma was detected as the unchanged form in a 60-min study. We concluded that [11C]TMSX PET has the potential for myocardial imaging.     

Quantitative analysis of dopamine transporters in human brain using [11C]PE2I and positron emission tomography: evaluation of reference tissue models

Objective

Dopamine transporter (DAT) is a reuptake carrier of dopamine at presynapse that regulates dopaminergic neural transmission. [¹¹C]PE2I is a cocaine analog developed as a potent positron emission tomography (PET) ligand for DAT with high selectivity. The aim of this study was to evaluate the applicability of quantification methods using reference tissue models for [¹¹C]PE2I.

Methods

Dynamic PET scans were performed in 6 young healthy male volunteers after an intravenous bolus injection of [¹¹C]PE2I. Metabolite-corrected arterial plasma-input functions were obtained. Compartment model analysis and plasma-input Logan analysis were performed to determine the kinetic parameters and distribution volume (V _T). The distribution volume ratio (DVR) was calculated as the ratio of V _T in the cerebral region to that in the cerebellum. DVRs were also determined by the original multilinear reference tissue model method (MRTMo) and the simplified reference tissue model method (SRTM), comparing the results with those obtained from graphical analysis using arterial input function. To estimate errors in DVR calculated using the reference tissue model, a simulation study that focused on cerebellar kinetics and scan duration was performed.

Results

The highest [¹¹C]PE2I binding was observed in the striatum, followed by the midbrain and thalamus. The 2-tissue model was preferable to the 1-tissue model for describing the [¹¹C]PE2I kinetics in the cerebellum. Both the measured and 90-min simulated data showed that reference tissue models caused an underestimation of DVR in the striatum. The simulation showed that 90-min scan duration was insufficient when cerebellar kinetics was described as a 1-tissue model. Nevertheless, DVR values determined by MRTMo and SRTM were in good agreement with those by the graphical approach in other lower binding regions.

Conclusion

Due to the [¹¹C]PE2I kinetics in the cerebellum and limited scan duration for ¹¹C, MRTMo and SRTM underestimated the striatal DVR. Despite this limitation, the present study demonstrated the applicability of reference tissue models. Since DAT in the midbrain and thalamus is of interest in the pathophysiology of neuropsychiatric disease, this noninvasive quantitative analysis will be useful for clinical investigations.     

Shortened protocol in practical [11C]SA4503-PET studies for sigma1 receptor quantification

In practical positron emission tomography (PET) diagnosis, a shortened protocol is preferred for patients with brain disorders. In this study, the applicability of a shortened protocol as an alternative to the 90-min PET scan with [¹¹C]SA4503 for quantitative sigma₁ receptor measurement was investigated. Tissue time-activity curves of 288 regions of interest in the brain from 32 [¹¹C]SA4503-PET scans of 16 healthy subjects prior to and following administration of a selective serotonin reuptake inhibitor (fluvoxamine or paroxetine) were applied to two algorithms of quantitative analysis; binding potential (BP) was derived from compartmental analysis based on nonlinear estimation, and total distribution volume (tDV) was derived from Logan plot analysis. As a result, although both BP and tDV tended to be underestimated by the shortened method, the estimates from the shortened protocol had good linear relationships with those of the full-length protocol. In conclusion, if approximately 10% differences in the estimated results are acceptable for a specific purpose, then a 60-min measurement protocol is capable of providing reliable results.     

Imaging of adenosine A<Subscript>1</Subscript> receptors in the human brain by positron emission tomography with [<Superscript>11</Superscript>C]MPDX

We report the first clinical PET study using [1-methyl-11C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine ([11C]MPDX) for imaging adenosine A1 receptors in the human brain. The binding of [11C]MPDX evaluated quantitatively as the distribution volume by a graphical analysis was high in the striatum and thalamus, and low in the cerebellum. The distribution pattern of [11C]MPDX was coincident with that of adenosine A1 receptors in vitro reported previously, and was different from those of blood flow and [18F]FDG. The [11C]MPDX PET has the potential for mapping adenosine A1 receptors in the human brain.     

Further characterization of a CNS adenosine A2a receptor ligand [11C]KF18446 within vitro autoradiography andin vivo tissue uptake

PET assessment of the adenosine A2a receptors localized in the striatum offers us a potential new diagnostic tool for neurological disorders. In the present study, we carried out in vitro receptor autoradiography of a newly developed PET ligand [11C]KF18446 ([7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthin e) with rat brain sections. [11C]KF18446 showed a high striatum/cortex binding ratio (5.0) and low nonspecific binding (<10%), suggesting that [11C]KF18446 has characteristics comparable or slightly superior to [3H]CGS 21680 or [3H]SCH 58261, which are currently available representative A2a receptor ligands. Scatchard analysis indicated a Kd of 9.8 nM and a Bmax of 170 fmol/mm3 tissue in the striatum and a Kd of 16.4 nM and a Bmax of 33 fmol/mm3 tissue in the cortex. Seven xanthine-type and four nonxanthine-type adenosine receptor ligands with an affinity for the adenosine A2a receptors significantly reduced the in vitro binding of [11C]KF18446 to the brain section. The blocking effects were much stronger in the striatum than in the cortex, but did not necessarily parallel their affinity. On the other hand, four xanthine-type ligands and one nonxanthine-type ligand (SCH 58261) of the 11 ligands studied reduced the in vivo uptake of [11C]KF18446 in mice, but other ligands, including A1-selective and nonselective ligands and three nonxanthine-type A2a-selective antagonists did not. We conclude that [11C]KF18446 is a promising adenosine A2a receptor ligand for PET study.     

Estimation of serotonin transporter parameters with 11C-DASB in healthy humans: reproducibility and comparison of methods.

The aim of the present study was to define the optimal analytic method to derive accurate and reliable serotonin transporter (SERT) receptor parameters with (11)C-3-amino-4-(2-[(dimethylamino)methyl]phenylthio)benzonitrile ((11)C-DASB). METHODS: Nine healthy subjects (5 females, 4 males) underwent two (11)C-DASB PET scans on the same day. Five analytic methods were used to estimate binding parameters in 10 brain regions: compartmental modeling with 1- and 2-tissue compartment models (1TC and 2TC), data-driven estimation of parametric images based on compartmental theory (DEPICT) analysis, graphical analysis, and the simplified reference tissue model (SRTM). Two variations in the fitting procedure of the SRTM method were evaluated: nonlinear optimization and basis function approach. The test/retest variability (VAR) and intraclass correlation coefficient (ICC or reliability) were assessed for 3 outcome measures: distribution volume (V(T)), binding potential (BP), and specific to nonspecific equilibrium partition coefficient (V(3)'). RESULTS: All methods gave similar values across all regions. The variability of V(T) was excellent (< or =10%) in all regions, for the 1TC, 2TC, DEPICT, and graphical approaches. The variability of BP and V(3)' was good in regions of high SERT density and poorer in regions of moderate and lower densities. The ICC of all 3 outcome measures was excellent in all regions. The basis function implementation of SRTM demonstrated improved reliability compared with nonlinear optimization, particularly in moderate and low-binding regions. CONCLUSION: The results of this study indicate that (11)C-DASB can be used to measure SERT parameters with high reliability and low variability in receptor-rich regions of the brain, with somewhat less reliability and increased variability in regions of moderate SERT density and poor reproducibility in low-density regions.     

Effects of image reconstruction algorithm on neurotransmission PET studies in humans: Comparison between filtered backprojection and ordered subsets expectation maximization

OBJECTIVES: Both reconstruction algorithms, filtered backprojection (FBP) and ordered subsets expectation maximization (OSEM), are widely used in clinical positron emission tomography (PET) studies. Image reconstruction for most neurotransmission PET scan data is performed by FBP, while image reconstruction for whole-body [18F]FDG scan data is usually performed by OSEM. Although several investigators have compared FBP and OSEM in terms of the quantification of regional radioactivity and physiological parameters calculated from PET data, only a few studies have compared the two reconstruction algorithms in PET studies that estimate neurotransmission, i.e., neuroreceptor and neurotransporter binding. In this study we compared mean regional radioactivity concentration in the late phase and binding potential (BP) between FBP and OSEM algorithms in neurotransmission PET studies for [11C]raclopride and [11C]DASB. METHODS: Dynamic PET scans with [11C]raclopride in 3-dimensional mode were performed on seven healthy subjects. Dynamic PET scans with [11C]DASB in 2-dimensional mode were performed on another seven subjects. OSEM images were post-filtered so that its transverse spatial resolution became similar to that of FBP with the same Hanning filter (Kernel FWHM 6 mm). In both PET studies we calculated the BP of [11C]raclopride and [11C]DASB by a reference tissue model for each ROI (region of interest). RESULTS: There was no significant difference in mean regional radioactivity concentration between FBP and OSEM for [11C]raclopride and [11C]DASB. Only +2.4 - +3.2%, but still a significant difference in BP of [11C]raclopride between FBP and OSEM was observed in the striatum. There was no significant difference in BP between FBP and OSEM in other than the striatum for [11C]raclopride and in all regions for [11C]DASB. In addition, there was no significant difference in root mean square error between FBP and OSEM when BP was calculated. CONCLUSIONS: The BP values were similar between FBP and OSEM algorithms with [11C]raclopride and [11C]DASB. This study indicates that OSEM can be used for human neurotransmission PET studies for calculating BP although OSEM was not necessarily superior to FBP in the present study.     

Quantification of adenosine A<Subscript>2A</Subscript> receptors in the human brain using [<Superscript>11</Superscript>C]TMSX and positron emission tomography

Purpose [7-methyl-¹¹C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([¹¹C]TMSX) is a positron-emitting adenosine A_2A receptor (A2AR) antagonist for visualisation of A2AR distribution by positron emission tomography (PET). The aims of this paper were to use a kinetic model to analyse the behaviour of [¹¹C]TMSX in the brain and to examine the applicability of the Logan plot. We also studied the applicability of a simplified Logan plot by omitting metabolite correction and arterial blood sampling. Methods The centrum semiovale was used as a reference region on the basis of a post-mortem study showing that it has a negligibly low density of A2ARs. Compartmental analysis was performed in five normal subjects. Parametric images of A2AR binding potential (BP) were also generated using a Logan plot with or without metabolite correction and with or without arterial blood sampling. To omit arterial blood sampling, we applied a method to extract the plasma-related information using independent component analysis (EPICA). Results The estimated K ₁/k ₂ was confirmed to be common in the centrum semiovale and main cortices. The three-compartment model was well fitted to the other regions using the fixed value of K ₁/k ₂ estimated from the centrum semiovale. The estimated BPs using the Logan plot matched those derived from compartment analysis. Without the metabolite correction, the estimate of BP underestimated the true value by 5%. The estimated BPs agreed regardless of arterial blood sampling. Conclusion A three-compartment model with a reference region, the centrum semiovale, describes the kinetic behaviour of [¹¹C]TMSX PET images. A2ARs in the human brain can be visualised as a BP image using [¹¹C]TMSX PET without arterial blood sampling.     

Characterization of [<Superscript>11</Superscript>C]Lu AE92686 as a PET radioligand for phosphodiesterase 10A in the nonhuman primate brain

Purpose

[¹¹C]Lu AE92686 is a positron emission tomography (PET) radioligand that has recently been validated for examining phosphodiesterase 10A (PDE10A) in the human striatum. [¹¹C]Lu AE92686 has high affinity for PDE10A (IC ₅₀?=?0.39 nM) and may also be suitable for examination of the substantia nigra, a region with low density of PDE10A. Here, we report characterization of regional [¹¹C]Lu AE92686 binding to PDE10A in the nonhuman primate (NHP) brain.

Methods

A total of 11 PET measurements, seven baseline and four following pretreatment with unlabeled Lu AE92686 or the structurally unrelated PDE10A inhibitor MP-10, were performed in five NHPs using a high resolution research tomograph (HRRT). [¹¹C]Lu AE92686 binding was quantified using a radiometabolite-corrected arterial input function and compartmental and graphical modeling approaches.

Results

Regional time-activity curves were best described with the two-tissue compartment model (2TCM). However, the distribution volume (V _T) values for all regions were obtained by the Logan plot analysis, as reliable cerebellar V _T values could not be derived by the 2TCM. For cerebellum, a proposed reference region, V _T values increased by ～30 % with increasing PET measurement duration from 63 to 123 min, while V _T values in target regions remained stable. Both pretreatment drugs significantly decreased [¹¹C]Lu AE92686 binding in target regions, while no significant effect on cerebellum was observed. Binding potential (BP _ND) values, derived with the simplified reference tissue model (SRTM), were 13–17 in putamen and 3–5 in substantia nigra and correlated well to values from the Logan plot analysis.

Conclusions

The method proposed for quantification of [¹¹C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [¹¹C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra.

     

Preclinical studies on [11C]MPDX for mapping adenosine A1 receptors by positron emission tomography

In previous in vivo studies with mice, rats and cats, we have demonstrated that [11C]MPDX ([1-methyl-11C]8-dicyclopropylmethyl-1-methyl-3-propylxanthine) is a potential radioligand for mapping adenosine A1 receptors of the brain by positron emission tomography (PET). In the present study, we performed a preclinical study. The radiation absorbed-dose by [11C]MPDX in humans estimated from the tissue distribution in mice was low enough for clinical use, and the acute toxicity and mutagenicity of MPDX were not found. The monkey brain was clearly visualized by PET with [11C]MPDX. We have concluded that [11C]MPDX is suitable for mapping adenosine A1 receptors in the human brain by PET.     

Quantitative measurement of histamine H(1) receptors in human brains by PET and [11C]doxepin

The aim of this study is to establish a method for quantitative measurement of histamine H(1) receptor (H1R) in human brain by PET and [(11)C]doxepin ([(11)C]DOX). The estimated parameters with a two-compartment model were stable for the initial values for parameter estimation but those with a three-compartment model were not. This finding suggests that the H1R measured by the [(11)C]DOX and PET can be evaluated with a two-compartment model.     

Preliminary evaluation of [1-11C]octanoate as a PET tracer for studying cerebral ischemia: A PET study in rat and canine models of focal cerebral ischemia

Octanoate is taken up into the brain and is converted in astrocytes to glutamine through the TCA cycle after beta-oxidation. We speculate that [1-11C]octanoate may be used as a tracer for astroglial functions and/or fatty acid metabolism in the brain and may be useful for studying cerebral ischemia. In the present study we investigated brain distribution of [1-11C]octanoate and compared it with cerebral blood flow (CBF) by using rat and canine models of middle cerebral artery (MCA) occlusion and a high resolution PET. In rats brain distribution of [15O]H2O measured 1-2 h and 5-6 h after insult was compared with that of [1-11C]octanoate measured 3-4 h after insult. Radioactivity ratios of lesioned to normal hemispheres determined with [15O]H2O were lower than those determined with [1-11C]octanoate. These results were confirmed by a study on a canine model of MCA-occlusion. Twenty-four hours after insult, CBF decreased in the MCA-territory of the occluded hemisphere, whereas normal or higher accumulation of [1-11C]octanoate was observed in the ischemic regions. The uptake of [1-11C]octanoate-derived radioactivity therefore increased relative to CBF in the ischemic regions, indicating that [1-11C]octanoate provides functional information different from CBF. In conclusion, we found that [1-11C]octanoate is a potential radiopharmaceutical for studying the pathophysiology of cerebral ischemia.     

Age-related changes of the binding of [<Superscript>3</Superscript>H]SA4503 to sigma<Subscript>1</Subscript> receptors in the rat brain

We have recently developed 1-([3-O-methyl-11C]3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine ([11C]SA4503) as a selective radioligand for mapping sigma1 receptors in the brain by positron emission tomography (PET). In the present short communication we evaluated the age-related changes of the binding of this ligand to sigma1 receptors in Fisher-344 rats (1.5-, 6-, 12-, and 24-month-old) by the in vitro binding assay. We also measured the binding of [3H](+)-pentazocine to sigma1 receptors and the binding of [3H]1,3-di-O-tolylguanidine to sigma2 receptors, which are current standard methods. The specific binding of the three radioligands increased age-dependently. Both Kd and Bmax values of the 24-month-old rats for each radioligand were significantly higher than those of the young rats (1.5- and 6-month-old). The increased numbers of both sigma1 and sigma2 receptor subtypes in the aged rats compensate for the lowered affinity, and rather enhanced the radioligand-receptor binding. The results contrast strikingly with the age-dependent decrease in the dopaminergic, cholinergic and glutamatergic receptors that are reported to be correlated with the sigma receptors, and indicate that a PET study with [11C]SA4503 to evaluate the aging process in humans would be of great interest.     

Quantification of GABAA receptors in the rat brain with [123I]Iomazenil SPECT from factor analysis-denoised images

PurposeIn vivo imaging of GABA_A receptors is essential for the comprehension of psychiatric disorders in which the GABAergic system is implicated. Small animal SPECT provides a modality for in vivo imaging of the GABAergic system in rodents using [¹²³I]Iomazenil, an antagonist of the GABA_A receptor. The goal of this work is to describe and evaluate different quantitative reference tissue methods that enable reliable binding potential (BP) estimations in the rat brain to be obtained.MethodsFive male Sprague–Dawley rats were used for [¹²³I]Iomazenil brain SPECT scans. Binding parameters were obtained with a one-tissue compartment model (1TC), a constrained two-tissue compartment model (2TC_c), the two-step Simplified Reference Tissue Model (SRTM2), Logan graphical analysis and analysis of delayed-activity images. In addition, we employed factor analysis (FA) to deal with noise in data.ResultsBP_ND obtained with SRTM2, Logan graphical analysis and delayed-activity analysis was highly correlated with BP_F values obtained with 2TC_c (r = 0.954 and 0.945 respectively, p < 0.0001). Equally significant correlations were found between values obtained with 2TC_c and SRTM2 in raw and FA-denoised images (r = 0.961 and 0.909 respectively, p < 0.0001). Scans of at least 100 min are required to obtain stable BP_ND values from raw images while scans of only 70 min are sufficient from FA-denoised images. These images are also associated with significantly lower standard errors of 2TC_c and SRTM2 BP values.ConclusionReference tissue methods such as SRTM2 and Logan graphical analysis can provide equally reliable BP_ND values from rat brain [¹²³I]Iomazenil SPECT. Acquisitions, however, can be much less time-consuming either with analysis of delayed activity obtained from a 20-minute scan 50 min after tracer injection or with FA-denoising of images.     

Preclinical studies on [<Superscript>11</Superscript>C]TMSX for mapping adenosine A<Subscript>2A</Subscript> receptors by positron emission tomography

In previous in vivo studies with mice, rats and monkeys, we have demonstrated that [11C]TMSX ([7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine) is a potential radioligand for mapping adenosine A2A receptors of the brain by positron emission tomography (PET). In the present study, we performed a preclinical study. A suitable preparation method for [11C]TMSX injection was established. The radiation absorbed-dose by [11C]TMSX in humans estimated from the tissue distribution in mice was low enough for clinical use, and the acute toxicity and mutagenicity of TMSX were not found. The striatal uptake of [11C]TMSX in mice was reduced by pretreatment with theophylline at the dose of 10 and 100 mg/kg, suggesting that the [11C]TMSX PET should be carefully performed in the patients received with theophylline. We have concluded that [11C]TMSX is suitable for mapping adenosine A2A receptors in the human brain by PET.     

Uptake of inflammatory cell marker [<Superscript>11</Superscript>C]PK11195 into mouse atherosclerotic plaques

Purpose  The ligand [¹¹C]PK11195 binds with high affinity and selectivity to peripheral benzodiazepine receptor, expressed in high amounts in macrophages. In humans, [¹¹C]PK11195 has been used successfully for the in vivo imaging of inflammatory processes of brain tissue. The purpose of this study was to explore the feasibility of [¹¹C]PK11195 in imaging inflammation in the atherosclerotic plaques. Methods  The presence of PK11195 binding sites in the atherosclerotic plaques was verified by examining the in vitro binding of [³H]PK11195 onto mouse aortic sections. Uptake of intravenously administered [¹¹C]PK11195 was studied ex vivo in excised tissue samples and aortic sections of a LDLR/ApoB48 atherosclerotic mice. Accumulation of the tracer was compared between the atherosclerotic plaques and non-atherosclerotic arterial sites by autoradiography and histological analyses. Results  The [³H]PK11195 was found to bind to both the atherosclerotic plaques and the healthy wall. The autoradiography analysis revealed that the uptake of [¹¹C]PK11195 to inflamed regions in plaques was more prominent (p = 0.011) than to non-inflamed plaque regions, but overall it was not higher than the uptake to the healthy vessel wall. Also, the accumulation of ¹¹C radioactivity into the aorta of the atherosclerotic mice was not increased compared to the healthy control mice. Conclusions  Our results indicate that the uptake of [¹¹C]PK11195 is higher in inflamed atherosclerotic plaques containing a large number of inflammatory cells than in the non-inflamed plaques. However, the tracer uptake to other structures of the artery wall was also prominent and may limit the use of [¹¹C]PK11195 in clinical imaging of atherosclerotic plaques.     

Initial characterization of a PDE10A selective positron emission tomography tracer [11C]AMG 7980 in non-human primates

IntroductionPhosphodiesterase 10A (PDE10A) is an intracellular enzyme responsible for the breakdown of cyclic nucleotides which are important secondary messengers in the central nervous system. Inhibition of PDE10A has been identified as a potential therapeutic target for treatment of various neuropsychiatric disorders. To assist the drug development program, we have identified a selective PDE10A PET tracer, [¹¹C]AMG 7980, for imaging PDE10A distribution using positron emission tomography.Methods[¹¹C]AMG 7980 was prepared in a one-pot, two-step reaction. Dynamic PET scans were performed in non-human primates following a bolus or bolus plus constant infusion tracer injection paradigm. Regions-of-interest were defined on individuals’ MRIs and transferred to the co-registered PET images. Data were analyzed using Logan graphical analysis with metabolite-corrected input function, the simplified reference tissue model (SRTM) method and occupancy plots. A benchmark PDE10A inhibitor was used to demonstrate PDE10A-specific binding.Results[¹¹C]AMG 7980 was prepared with a mean specific activity of 99 ± 74 GBq/μmol (n = 10) and a synthesis time of 45 min. Specific binding of the tracer was localized to the striatum and globus pallidus (GP) and low in other brain regions. Thalamus was used as the reference tissue to derive binding potentials (BP_ND). The BP_ND for caudate, putamen, and GP were 0.23, 0.65, 0.51, respectively by the graphical method, and 0.42, 0.76, and 0.75 from the SRTM method. A dose dependent decrease of BP_ND was observed with the pre-treatment of a PDE10A inhibitor. A bolus plus infusion injection paradigm yielded similar results.Conclusion[¹¹C]AMG 7980 has been successfully used for imaging PDE10A in non-human primate brain. Despite the fast brain kinetics it can be used to measure target occupancy of PDE10A inhibitors in non-human primates and potentially applicable to humans.     

Age-related changes of the [11C]CFT binding to the striatal dopamine transporters in the Fischer 344 rats: a PET study

We investigated the age-related changes of the binding of [11C]CFT to striatal dopamine transporters (DATs) in vivo in Fischer 344 rats by positron emission tomography (PET). The tissue dissection method represented an age-related decrease in the uptake ratio of the striatum to the cerebellum and in the specific binding-to-nonspecific binding ratio of [11C]CFT. PET demonstrated an age-dependent decrease in the striatal uptake of [11C]CFT, however, the kinetic analysis represented the age-related decrease in both the association rate constant (k3) and dissociation rate constant (k4), but not the binding potential (k3/k4) that was a parameter including both of density and affinity of the binding sites. The PET finding was not necessarily coincident with the result investigated in vitro previously. Therefore, careful interpretation is necessary for PET studies using [11C]CFT and small animals such as rats.     

Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis.

PET studies have been performed using the amyloid binding radiotracer Pittsburgh Compound B (PIB). Previous quantitative analyses using arterial blood showed that the Logan graphical analysis using 90 min of emission data (ART90) provided a reliable measure of PIB retention. This work reports on simplified methods of analysis for human PIB imaging. METHODS: PIB PET scans were conducted in 24 subjects (6 Alzheimer's disease [AD], 10 mild cognitive impairment [MCI], 8 controls) with arterial blood sampling. Retest scans were performed on 8 subjects (3 AD, 1 MCI, 4 controls) within 28 d. Data were analyzed over 60 and 90 min using the Logan analysis and (a) metabolite-corrected input functions based on arterial plasma (ART60, ART90), (b) carotid artery time-activity data with a population average metabolite correction (CAR60, CAR90); and (c) cerebellar reference tissue (CER60, CER90). Data also were analyzed using the simplified reference tissue method (SRTM60, SRTM90) and a single-scan method based on late-scan ratios of standardized uptake values (SUVR60, SUVR90). RESULTS: All methods of analysis examined effectively discerned regional differences between AD and control subjects in amyloid-laden cortical regions, although the performance of the simplified methods varied in terms of bias, test-retest variability, intersubject variability, and effect size. CAR90 best agreed with ART90 distribution volume ratio (DVR) measures across brain regions and subject groups and demonstrated satisfactory test-retest variability (+/-7.1% across regions). CER90 and CER60 showed negative biases relative to ART90 in high-DVR subjects but had the lowest test-retest variability. The single-scan SUV-based methods showed the largest effect sizes for AD and control group differences and performed well in terms of intersubject and test-retest variability. CONCLUSION: Of the simplified methods for PIB analysis examined, CAR90 provided DVR measures that were most comparable to ART90; CER90 was the most reproducible and SUVR90 produced the largest effect size. All simplified methods were effective at distinguishing AD and control differences and may be effectively used in the analysis of PIB. SUVR60 data can be obtained with as little as 20 min of PET emission data collection. The relative strengths and limitations of each method must be considered for each experimental design.