Test-retest variability of quantitative [<Superscript>11</Superscript>C]PIB studies in Alzheimer’s disease

Purpose  

The aim of this study was to assess the test-retest variability of [¹¹C]PIB studies in patients with Alzheimer’s disease (AD) and healthy controls using several tracer kinetic models and to assess the suitability of the cerebellum as reference tissue.     

A comparison of five partial volume correction methods for Tau and Amyloid PET imaging with [<Superscript>18</Superscript>F]THK5351 and [<Superscript>11</Superscript>C]PIB

Purpose

To suppress partial volume effect (PVE) in brain PET, there have been many algorithms proposed. However, each methodology has different property due to its assumption and algorithms. Our aim of this study was to investigate the difference among partial volume correction (PVC) method for tau and amyloid PET study.

Methods

We investigated two of the most commonly used PVC methods, Müller-Gärtner (MG) and geometric transfer matrix (GTM) and also other three methods for clinical tau and amyloid PET imaging. One healthy control (HC) and one Alzheimer’s disease (AD) PET studies of both [¹⁸F]THK5351 and [¹¹C]PIB were performed using a Eminence STARGATE scanner (Shimadzu Inc., Kyoto, Japan). All PET images were corrected for PVE by MG, GTM, Labbé (LABBE), Regional voxel-based (RBV), and Iterative Yang (IY) methods, with segmented or parcellated anatomical information processed by FreeSurfer, derived from individual MR images. PVC results of 5 algorithms were compared with the uncorrected data.

Results

In regions of high uptake of [¹⁸F]THK5351 and [¹¹C]PIB, different PVCs demonstrated different SUVRs. The degree of difference between PVE uncorrected and corrected depends on not only PVC algorithm but also type of tracer and subject condition.

Conclusion

Presented PVC methods are straight-forward to implement but the corrected images require careful interpretation as different methods result in different levels of recovery.

     

The prognostic value of [<Superscript>123</Superscript>I]-vascular endothelial growth factor ([<Superscript>123</Superscript>I]-VEGF) in glioma

Purpose

Recent studies have shown that tumor vascular endothelial cells and various tumor cells overexpress receptors for vascular endothelial growth factor (VEGF). The aim of this study was to investigate the prognostic value of [¹²³I]-VEGF scintigraphy in patients with histologically verified brain tumors.

Methods

23 consecutive patients (9 women and 14 men aged 30–83 years, mean age 56.6 ± 14.4 years) with histopathologically-verified primary brain tumors were included in the study. All patients had undergone [¹²³I]-VEGF scintigraphy. SPECT examinations of brain were performed 30 min and 18 h after injection. Additional [¹¹C]-methionine PET ([¹¹C]-MET PET) was performed in eight of the 23 patients. Both [¹²³I]-VEGF and [¹¹C]-MET PET were evaluated visually and semiquantitatively by tumor-to-normal brain uptake ratio (T/N ratio). Thresholds of the T/N ratio were evaluated by analysis of receiver operating characteristics (ROC). Overall survival (OS) was estimated using the Kaplan-Meier method.

Results

World Health Organization (WHO) grade IV glioma lesions showed [¹²³I]-VEGF uptake 18 h after the injection, whereas other brain tumors of grade II or III showed negative results. There was no significant difference in the tumor size between VEGF positive and VEGF negative tumors. Patients with [¹²³I]-VEGF T/N ratio threshold <1.32 showed significantly longer survival than patients with T/N ratio?≥?1.32 (2680 days vs 295 days; P?<?0.05). In the subgroup of 16 grade IV glioma patients, significant OS differences were found using a T/N ratio of 1.75 as threshold (T/N ratio?<?1.75: 720 days; T/N?≥?1.75: 183 days; P?<?0.05). Significant difference (P?<?0.05) was also found in [¹¹C]-MET PET T/N ratios between the grade IV glioma (mean T/N ratio: 3.71) and the grade II or III glioma (mean T/N ratio: 1.74).

Conclusion

Our results suggest that [¹²³I]-VEGF scintigraphy may be useful for visualization of tumor angiogenesis. In addition, [¹²³I]-VEGF may provide relevant prognostic information in patients with glioma.

     

Two activated stages of microglia and PET imaging of peripheral benzodiazepine receptors with [<Superscript>11</Superscript>C]PK11195 in rats

Objective  

The transition of microglia from the normal resting state to the activated state is associated with an increased expression of peripheral benzodiazepine receptors (PBR). The extent of PBR expression is dependent on the level of microglial activation. A PBR ligand, [¹¹C]PK11195, has been used for imaging of the activation of microglia in vivo. We evaluated whether [¹¹C]PK11195 PET can indicate differences of microglial activation between no treatment and lipopolysaccharide (LPS) treatment in a rat artificial injury model of brain inflammation.     

First automatic radiosynthesis of <Superscript>11</Superscript>C labeled Telmisartan using a multipurpose synthesizer for clinical research use

Objective  

Telmisartan, a nonpeptide angiotensin II AT1 receptor antagonist, is an antihypertensive drug. Positron emission tomography (PET) imaging with [¹¹C]Telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as the transport function of hepatic OATP1B3. We developed a first automatic preparation system of [¹¹C]Telmisartan to applicable clinical research using a new ¹¹C and ¹⁸F multipurpose synthesizer.     

The value of [<Superscript>11</Superscript>C]-acetate PET and [<Superscript>18</Superscript>F]-FDG PET in hepatocellular carcinoma before and after treatment with transarterial chemoembolization and bevacizumab

Purpose

This prospective study was to investigate the value of [¹¹C]-acetate PET and [¹⁸F]-FDG PET in the evaluation of hepatocellular carcinoma (HCC) before and after treatment with transarterial chemoembolization (TACE) and vascular endothelial growth factor (VEGF) antibody (bevacizumab).

Methods

Twenty-two patients (three women, 19 men; 62 ± 8 years) with HCC verified by histopathology were treated with TACE and bevacizumab (n = 11) or placebo (n = 11). [¹¹C]-acetate PET and [¹⁸F]-FDG PET were performed before and after TACE with bevacizumab or placebo. Comparisons between groups were performed with t-tests and Chi-squared tests, where appropriate. Overall survival (OS) was defined as the time from start of bevacizumab or placebo until the date of death/last follow-up, respectively.

Results

The patient-related sensitivity of [¹¹C]-acetate PET, [¹⁸F]-FDG PET, and combined [¹¹C]-acetate and [¹⁸F]-FDG PET was 68%, 45%, and 73%, respectively. There was a significantly higher rate of conversion from [¹¹C]-acetate positive lesions to negative lesions in patients treated with TACE and bevacizumab as compared with that in patients with TACE and placebo (p < 0.05). In patients with negative acetate PET, the mean OS in patients treated with TACE and bevacizumab was 259 ± 118 days and was markedly shorter as compared with that (668 ± 217 days) in patients treated with TACE and placebo (p < 0.05). In patients treated with TACE and placebo, there was significant difference in mean OS in patients with positive FDG PET as compared with that in patients with negative FDG PET (p < 0.05). The HCC lesions had different tracer avidities showing the heterogeneity of HCC.

Conclusions

Our study suggests that combining [¹⁸F]-FDG with [¹¹C]-acetate PET could be useful for the management of HCC patients and might also provide relevant prognostic and molecular heterogeneity information.

     

Preclinical and first-in-man studies of [<Superscript>11</Superscript>C]CB184 for imaging the 18-kDa translocator protein by positron emission tomography

Objective

We performed preclinical and first-in-man clinical positron emission tomography (PET) studies in human brain using N,N-di-n-propyl-2-[2-(4-[¹¹C]methoxyphenyl)-6,8-dichloroimidazol[1,2-a]pyridine-3-yl]acetamide ([¹¹C]CB184) to image the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia in neuroinflammatory conditions.

Methods

In vitro selectivity of CB184 was characterized. The radiation absorbed dose by [¹¹C]CB184 in humans was calculated from murine distribution data. Acute toxicity of CB184 hydrochloride in rats at a dose of 5.81 mg/kg body weight, which is >10,000-fold higher than the clinical equivalent dose of [¹¹C]CB184, was evaluated. Acute toxicity of [¹¹C]CB184 injection of a 400-fold dose to administer a postulated dose of 740 MBq [¹¹C]CB184 was also evaluated after the decay-out of ¹¹C. The mutagenicity of CB184 was studied with a reverse mutation test (Ames test). The pharmacological effect of CB184 injection in mice was studied with an open field test. The first PET imaging of TSPO with [¹¹C]CB184 in a normal human volunteer was performed.

Results

A suitable preparation method for [¹¹C]CB184 injection was established. CB184 showed low activity in a 28-standard receptor binding profile. The radiation absorbed dose by [¹¹C]CB184 in humans was sufficiently low for clinical use, and no acute toxicity of CB184 or [¹¹C]CB184 injection was found. No mutagenicity or apparent effect on locomotor activity or anxiety status was observed for CB184. We safely performed brain imaging with PET following administration of [¹¹C]CB184 in a normal human volunteer. A 90-min dynamic scan showed rapid initial uptake of radioactivity in the brain followed by prompt clearance. [¹¹C]CB184 was homogeneously distributed in the gray matter. The total distribution volume of [¹¹C]CB184 was highest in the thalamus followed by the cerebellar cortex and elsewhere. Although regional differences were small, the observed [¹¹C]CB184 binding pattern was consistent with the TSPO distribution in normal human brain. Peripherally, [¹¹C]CB184 was metabolized in humans: 30 % of the radioactivity in plasma was detected as the unchanged form after 60 min.

Conclusions

[¹¹C]CB184 is suitable for imaging TSPO in human brain and provides an acceptable radiation dose. Pharmacological safety was noted at the dose required for PET imaging.

     

Potential of [<Superscript>11</Superscript>C]acetate for measuring myocardial blood flow: Studies in normal subjects and patients with hypertrophic cardiomyopathy

Background  

Measuring the rate of clearance of carbon-11 labelled acetate from myocardium using positron emission tomography (PET) is an accepted technique for noninvasively assessing myocardial oxygen consumption. Initial myocardial uptake of [¹¹C]acetate, however, is related to myocardial blood flow (MBF) and several tracer kinetic models for quantifying MBF using [¹¹C]acetate have been proposed. The objective of this study was to assess these models.     

Quantification of receptor-ligand binding with [<Superscript>18</Superscript>F]fluciclatide in metastatic breast cancer patients

Purpose  

The purpose of the study was to estimate the receptor-ligand binding of an arginine-glycine-aspartic acid (RGD) peptide in somatic tumours. To this aim, we employed dynamic positron emission tomography (PET) data obtained from breast cancer patients with metastases, studied with the α_vβ_3/5 integrin receptor radioligand [¹⁸F]fluciclatide.     

Synthesis and evaluation of a new vesamicol analog <Emphasis Type="Italic">o</Emphasis>-[<Superscript>11</Superscript>C]methyl-<Emphasis Type="Italic">trans</Emphasis>-decalinvesamicol as a PET ligand for the vesicular acetylcholine transporter

Introduction

We focused on the vesicle acetyl choline transporter (VAChT) as target for early diagnosis of Alzheimer’s diseases because the dysfunction of the cholinergic nervous system is closely associated with the symptoms of AD, such as problem in recognition, memory, and learning. Due to its low binding affinity for the sigma receptors (σ-1 and σ-2), o-methyl-trans-decalinvesamicol (OMDV) demonstrated a high binding affinity and selectivity for vesicular acetyl choline transporter (VAChT). [¹¹C]OMDV was prepared and investigated the potential as a new PET ligand for VAChT imaging through in vivo evaluation.

Method

[¹¹C]OMDV was prepared by a palladium-promoted cross-coupling reaction using [¹¹C]methyl iodide, with a radiochemical yield of 60–75 %, a radiochemical purity of greater than 98 %, and a specific activity of 5–10 TBq/mmol 30 min after EOB. In vivo biodistribution study of [¹¹C]OMDV in blood, brain regions and major organs of rats was performed at 2, 10, 30 and 60 min post-injection. In vivo blocking study and PET–CT imaging study were performed to check the binding selectivity of [¹¹C]OMDV for VAChT.

Results

In vivo studies demonstrated [¹¹C]OMDV passage through the blood–brain barrier (BBB) and accumulation in the rat brain. The regional brain accumulation of [¹¹C]OMDV was significantly inhibited by co-administration of vesamicol. In contrast, brain accumulation of [¹¹C]OMDV was not significantly altered by co-administration of (+)-pentazocine, a selective σ-1 receptor ligand, or (+)-3-(3-hydroxyphenyl)-N-propylpiperidine [(+)-3-PPP], a σ-1 and σ-2 receptor ligand. PET–CT imaging revealed inhibition of [¹¹C]OMDV accumulation in the brain by co-administration of vesamicol.

Conclusion

[¹¹C]OMDV selectively binds to VAChT with high affinity in the rat brain in vivo, and that [¹¹C]OMDV may be utilized in the future as a specific VAChT ligand for PET imaging.

     

Pharmacokinetics of [18F]flutemetamol in wild-type rodents and its binding to beta amyloid deposits in a mouse model of Alzheimer’s disease

Purpose

The aim of this study was to investigate the potential of [¹⁸F]flutemetamol as a preclinical PET tracer for imaging β-amyloid (Aβ) deposition by comparing its pharmacokinetics to those of [¹¹C]Pittsburgh compound B ([¹¹C]PIB) in wild-type Sprague Dawley rats and C57Bl/6N mice. In addition, binding of [¹⁸F]flutemetamol to Aβ deposits was studied in the Tg2576 transgenic mouse model of Alzheimer’s disease.

Methods

[¹⁸F]Flutemetamol biodistribution was evaluated using ex vivo PET methods and in vivo PET imaging in wild-type rats and mice. Metabolism and binding of [¹¹C]PIB and [¹⁸F]flutemetamol to plasma proteins were analysed using thin-layer chromatography and ultrafiltration methods, respectively. Radiation dose estimates were calculated from rat ex vivo biodistribution data. The binding of [¹⁸F]flutemetamol to Aβ deposits was also studied using ex vivo and in vitro autoradiography. The location of Aβ deposits in the brain was determined with thioflavine S staining and immunohistochemistry.

Results

The pharmacokinetics of [¹⁸F]flutemetamol resembled that of [¹¹C]PIB in rats and mice. In vivo studies showed that both tracers readily entered the brain, and were excreted via the hepatobiliary pathway in both rats and mice. The metabolism of [¹⁸F]flutemetamol into radioactive metabolites was faster than that of [¹¹C]PIB. [¹⁸F]Flutemetamol cleared more slowly from the brain than [¹¹C]PIB, particularly from white matter, in line with its higher lipophilicity. Effective dose estimates for [¹¹C]PIB and [¹⁸F]flutemetamol were 2.28 and 6.65?μSv/MBq, respectively. Autoradiographs showed [¹⁸F]flutemetamol binding to fibrillar Aβ deposits in the brain of Tg2576 mice.

Conclusion

Based on its pharmacokinetic profile, [¹⁸F]flutemetamol showed potential as a PET tracer for preclinical imaging. It showed good brain uptake and was bound to Aβ deposits in the brain of Tg2576 mice. However, its high lipophilicity might complicate the analysis of PET data, particularly in small-animal imaging.     

Evaluation of ECG-gated [<Superscript>11</Superscript>C]acetate PET for measuring left ventricular volumes,mass, and myocardial external efficiency

Background

Noninvasive estimation of myocardial external efficiency (MEE) requires measurements of left ventricular (LV) oxygen consumption with [¹¹C]acetate PET in addition to LV stroke volume and mass with cardiovascular magnetic resonance (CMR). Measuring LV geometry directly from ECG-gated [¹¹C]acetate PET might enable MEE evaluation from a single PET scan. Therefore, we sought to establish the accuracy of measuring LV volumes, mass, and MEE directly from ECG-gated [¹¹C]acetate PET.

Methods

Thirty-five subjects with aortic valve stenosis underwent ECG-gated [¹¹C]acetate PET and CMR. List mode PET data were rebinned into 16-bin ECG-gated uptake images before measuring LV volumes and mass using commercial software and compared to CMR. Dynamic datasets were used for calculation of mean LV oxygen consumption and MEE.

Results

LV mass, volumes, and ejection fraction measured by CMR and PET correlated strongly (r = 0.86-0.92, P < .001 for all), but were underestimated by PET (P < .001 for all except ESV P = .79). PET-based MEE, corrected for bias, correlated fairly with PET/CMR-based MEE (r = 0.60, P < .001, bias ?3 ± 21%, P = .56). PET-based MEE bias was strongly associated with LV wall thickness.

Conclusions

Although analysis-related improvements in accuracy are recommended, LV geometry estimated from ECG-gated [¹¹C]acetate PET correlate excellently with CMR and can indeed be used to evaluate MEE.

     

PET imaging of focal demyelination and remyelination in a rat model of multiple sclerosis: comparison of [11C]MeDAS, [11C]CIC and [11C]PIB

Purpose

In this study, we compared the ability of [¹¹C]CIC, [¹¹C]MeDAS and [¹¹C]PIB to reveal temporal changes in myelin content in focal lesions in the lysolecithin rat model of multiple sclerosis. Pharmacokinetic modelling was performed to determine the best method to quantify tracer uptake.

Methods

Sprague-Dawley rats were stereotactically injected with either 1 % lysolecithin or saline into the corpus callosum and striatum of the right brain hemisphere. Dynamic PET imaging with simultaneous arterial blood sampling was performed 7 days after saline injection (control group), 7 days after lysolecithin injection (demyelination group) and 4 weeks after lysolecithin injection (remyelination group).

Results

The kinetics of [¹¹C]CIC, [¹¹C]MeDAS and [¹¹C]PIB was best fitted by Logan graphical analysis, suggesting that tracer binding is reversible. Compartment modelling revealed that all tracers were fitted best with the reversible two-tissue compartment model. Tracer uptake and distribution volume in lesions were in agreement with myelin status. However, the slow kinetics and homogeneous brain uptake of [¹¹C]CIC make this tracer less suitable for in vivo PET imaging. [¹¹C]PIB showed good uptake in the white matter in the cerebrum, but [¹¹C]PIB uptake in the cerebellum was low, despite high myelin density in this region. [¹¹C]MeDAS distribution correlated well with myelin density in different brain regions.

Conclusion

This study showed that PET imaging of demyelination and remyelination processes in focal lesions is feasible. Our comparison of three myelin tracers showed that [¹¹C]MeDAS has more favourable properties for quantitative PET imaging of demyelinated and remyelinated lesions throughout the CNS than [¹¹C]CIC and [¹¹C]PIB.     

Reproducibility study of [<Superscript>18</Superscript>F]FPP(RGD)<Subscript>2</Subscript> uptake in murine models of human tumor xenografts

Purpose  

An ¹⁸F-labeled PEGylated arginine-glycine-aspartic acid (RGD) dimer {[¹⁸F]FPP(RGD)₂} has been used to image tumor α_vβ₃ integrin levels in preclinical and clinical studies. Serial positron emission tomography (PET) studies may be useful for monitoring antiangiogenic therapy response or for drug screening; however, the reproducibility of serial scans has not been determined for this PET probe. The purpose of this study was to determine the reproducibility of the integrin α_vβ₃-targeted PET probe, [¹⁸F]FPP(RGD)_2, using small animal PET.     

Identification and regional distribution in rat brain of radiometabolites of the dopamine transporter PET radioligand [<Superscript>11</Superscript>C]PE2I

Purpose We aimed to determine the composition of radioactivity in rat brain after intravenous administration of the dopamine transporter radioligand, [¹¹C]PE2I. Methods PET time-activity curves (TACs) and regional brain distribution ex vivo were measured using no-carrier-added [¹¹C]PE2I. Carrier-added [¹¹C]PE2I was administered to identify metabolites with high-performance liquid radiochromatography (RC) or RC with mass spectrometry (LC-MS and MS-MS). The stability of [¹¹C]PE2I was assessed in rat brain homogenates. Results After peak brain uptake of no-carrier-added [¹¹C]PE2I, there was differential washout rate from striata and cerebellum. Thirty minutes after injection, [¹¹C]PE2I represented 10.9 ± 2.9% of the radioactivity in plasma, 67.1 ± 11.0% in cerebellum, and 92.5 ± 3.2% in striata, and was accompanied by two less lipophilic radiometabolites. [¹¹C]PE2I was stable in rat brain homogenate for at least 1 h at 37°C. LC-MS identified hydroxylated PE2I (1) (m/z 442) and carboxyl-desmethyl-PE2I (2) (m/z 456) in brain. MS-MS of 1 gave an m/z 442→424 transition due to H₂O elimination, so verifying the presence of a benzyl alcohol group. Metabolite 2 was the benzoic acid derivative. Ratios of ex vivo measurements of [¹¹C]PE2I, [¹¹C]1, and [¹¹C]2 in striata to their cognates in cerebellum were 6.1 ± 3.4, 3.7 ± 2.2 and 1.33 ± 0.38, respectively, showing binding selectivity of metabolite [¹¹C]1 to striata. Conclusion Radiometabolites [¹¹C]1 and [¹¹C]2 were characterized as the 4-hydroxymethyl and 4-carboxyl analogs of [¹¹C]PE2I, respectively. The presence of the pharmacologically active [¹¹C]1 and the inactive [¹¹C]2 is a serious impediment to successful biomathematical analysis.     

Synthesis and preclinical evaluation of [<Superscript>11</Superscript>C]PAQ as a PET imaging tracer for VEGFR-2

Purpose  (R,S)-N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolinamine (PAQ) is a tyrosine kinase inhibitor with high affinity for the vascular endothelial growth factor receptor 2 (VEGFR-2), which plays an important role in tumour angiogenesis. The aim of this work was to develop and evaluate in mice the ¹¹C-labelled analogue as an in vivo tracer for VEGFR-2 expression in solid tumours. Methods  [¹¹C]PAQ was synthesized by an N-methylation of desmethyl-PAQ using [¹¹C]methyl iodide. The tracer’s pharmacokinetic properties and its distribution in both subcutaneous and intraperitoneal tumour models were evaluated with positron emission tomography (PET). [¹⁸F]FDG was used as a reference tracer for tumour growth. PET results were corroborated by ex vivo and in vitro phosphor imaging and immunohistochemical analyses. Results  In vitro assays and PET in healthy animals revealed low tracer metabolism, limited excretion over 60 min and a saturable and irreversible binding. Radiotracer uptake in subcutaneous tumour masses was low, while focal areas of high uptake (up to 8% ID/g) were observed in regions connecting the tumour to the host. Uptake was similarly high but more distributed in tumours growing within the peritoneum. The pattern of radiotracer uptake was generally different from that of the metabolic tracer [¹⁸F]FDG and correlated well with variations in VEGFR-2 expression determined ex vivo by immunohistochemical analysis. Conclusion  These results suggest that [¹¹C]PAQ has potential as a noninvasive PET tracer for in vivo imaging of VEGFR-2 expression in angiogenic “hot spots”.     

A Single Intraperitoneal Injection of Endotoxin Changes Glial Cells in Rats as Revealed by Positron Emission Tomography Using [<Superscript>11</Superscript>C]PK11195

Purpose

Intracranial administration of lipopolysaccharide (LPS) is known to elicit a rapid innate immune response, activate glial cells in the brain, and induce depression-like behavior. However, no study has focused on the changes in glial cells induced by intraperitoneal injection of LPS in vivo.

Methods

Ten adult male Fischer F344 rats underwent [¹¹C]PK11195 PET before and 2 days after intraperitoneal injection of LPS to evaluate the changes in glial cells. The difference in standardized uptake values (SUV) of [¹¹C]PK11195 between before and after injection was determined.

Results

There was a cluster of brain regions that showed significant reductions in SUV. This cluster included the bilateral striata and bilateral frontal regions, especially the somatosensory areas.

Conclusions

Changes in activity of glial cells induced by the intraperitoneal injection of LPS were detected in vivo by [¹¹C]PK11195 PET. Intraperitoneal injection of LPS is known to induce depression, and further studies with [¹¹C]PK11195 PET would clarify the relationships between neuroinflammation and depression.

     

Positron emission tomography inter-scanner differences in dopamine D<Subscript>2</Subscript> receptor binding measured with [<Superscript>11</Superscript>C]FLB457

Objective  

It is well known that the positron emission tomography (PET) system is subject to inter-scanner differences of regional radioactivity distribution. In the present study, the effect of inter-scanner difference of regional radioactivity on estimated binding potential (BP_ND) of [¹¹C]FLB457 using the simplified reference tissue model (SRTM) was investigated.     

In vivo positron emission tomography imaging with [<Superscript>11</Superscript>C]ABP688: binding variability and specificity for the metabotropic glutamate receptor subtype 5 in baboons

Purpose  

Metabotropic glutamate receptor subtype 5 (mGluR5) dysfunction has been implicated in several disorders. [¹¹C]ABP688, a positron emission tomography (PET) ligand targeting mGluR5, could be a valuable tool in the development of novel therapeutics for these disorders by establishing in vivo drug occupancy. Due to safety concerns in humans, these studies may be performed in nonhuman primates. Therefore, in vivo characterization of [¹¹C]ABP688 in nonhuman primates is essential.     

[<Superscript>11</Superscript>C]TASP457, a novel PET ligand for histamine H<Subscript>3</Subscript> receptors in human brain

Purpose

The histamine H₃ receptors are presynaptic neuroreceptors that inhibit the release of histamine and other neurotransmitters. The receptors are considered a drug target for sleep disorders and neuropsychiatric disorders with cognitive decline. We developed a novel PET ligand for the H₃ receptors, [¹¹C]TASP0410457 ([¹¹C]TASP457), with high affinity, selectivity and favorable kinetic properties in the monkey, and evaluated its kinetics and radiation safety profile for quantifying the H₃ receptors in human brain.

Methods

Ten healthy men were scanned for 120 min with a PET scanner for brain quantification and three healthy men were scanned for radiation dosimetry after injection of 386?±?6.2 MBq and 190?±?7.5 MBq of [¹¹C]TASP457, respectively. For brain quantification, arterial blood sampling and metabolite analysis were performed using high-performance liquid chromatography. Distribution volumes (V _T) in brain regions were determined by compartment and graphical analyses using the Logan plot and Ichise multilinear analysis (MA1). For dosimetry, radiation absorbed doses were estimated using the Medical Internal Radiation Dose scheme.

Results

[¹¹C]TASP457 PET showed high uptake (standardized uptake values in the range of about 3 – 6) in the brain and fast washout in cortical regions and slow washout in the pallidum. The two-tissue compartment model and graphical analyses estimated V _T with excellent identification using 60-min scan data (about 16 mL/cm³ in the pallidum, 9 – 14 in the basal ganglia, 6 – 9 in cortical regions, and 5 in the pons), which represents the known distribution of histamine H₃ receptors. For parametric imaging, MA1 is recommended because of minimal underestimation with small intersubject variability. The organs with the highest radiation doses were the pancreas, kidneys, and liver. The effective dose delivered by [¹¹C]TASP457 was 6.9 μSv/MBq.

Conclusion

[¹¹C]TASP457 is a useful novel PET ligand for the investigation of the density of histamine H₃ receptors in human brain.