Potential Effect of Prolonged Sevoflurane Anesthesia on the Kinetics of [<Superscript>11</Superscript>C]Raclopride in Non-human Primates

Purpose

Positron emission tomography (PET) in non-human primates (NHP) is commonly performed under anesthesia, with sevoflurane being a widely used inhaled anesthetic. PET measurement in NHP can be repeated, and a difference in radioligand kinetics has previously been observed between the first and second PET measurement on the same day using sevoflurane anesthesia. In this study, we evaluated the effect of prolonged sevoflurane anesthesia on kinetics and binding potential (BP_ND) of [¹¹C]raclopride in NHP.

Procedures

Three cynomolgus monkeys underwent two to three PET measurements with [¹¹C]raclopride under continuous sevoflurane anesthesia on the same day. The concentration of sevoflurane was adjusted according to the general conditions and safety parameters of the NHP. Time to peak (TTP) radioactivity in the striatum was estimated from time-activity curves (TACs). The BP_ND in the striatum was calculated by the simplified reference tissue model using the cerebellum as reference region.

Results

In each NHP, the TTP became shorter in the later PET measurements than in the first one. Across all measurements (n = 8), concentration of sevoflurane correlated with TTP (Spearman’s ρ = ? 0.79, p = 0.03), but not with BP_ND (ρ = ? 0.25, p = 0.55).

Conclusions

These data suggest that sevoflurane affects the shape of TACs but has no evident effect on BP_ND in consecutive PET measurements.

     

A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[<Superscript>11</Superscript>C]Rolipram

Purpose

Phosphodiesterase 4 (PDE4) inhibition in the brain has been reported to improve cognitive function in animal models. Therefore, PDE4 inhibitors are one of key targets potential for drug development. Investigation of brain PDE4 occupancy would help to understand the effects of PDE4 inhibition to cognitive functions. Roflumilast is a selective phosphodiesterase type 4 (PDE4) inhibitor used clinically for severe chronic obstructive pulmonary disease, but the effects to the brain have not been well investigated. In this study, we aimed to investigate whether roflumilast entered the brain and occupied PDE4 in nonhuman primates.

Procedures

Positron emission tomography (PET) measurements with (R)-[¹¹C]rolipram were performed at baseline and after intravenous (i.v.) administration of roflumilast (3.6 to 200 μg/kg) in three female rhesus monkeys. Arterial blood samples were taken to obtain the input function. Protein binding was measured to obtain the free fraction (fp) of the radioligand. Total distribution volume (V_T) and V_T/fp were calculated as outcome measures from two tissue compartment model. Lassen plot approach was taken to estimate the target occupancy.

Results

The brain uptake of (R)-[¹¹C]rolipram decreased after roflumilast administration. PDE 4 occupancy by roflumilast showed dose- and plasma concentration-dependent increase, although PDE4 occupancy did not reach 50 % even after the administration of up to 200 μg/kg of roflumilast, regardless of outcome measures, V_T or V_T/fp.

Conclusions

This PET study showed that the brain PDE4 binding was blocked to a certain extent after i.v. administration of clinical relevant doses of roflumilast in nonhuman primates. Further clinical PET evaluation is needed to understand the relationship between PDE4 inhibition and potential improvement of cognitive function in human subjects.

     

Sigma-1 Agonist Binding in the Aging Rat Brain: a MicroPET Study with [<Superscript>11</Superscript>C]SA4503

Purpose

Sigma-1 receptor ligands modulate the release of several neurotransmitters and intracellular calcium signaling. We examined the binding of a radiolabeled sigma-1 agonist in the aging rat brain with positron emission tomography (PET).

Procedures

Time-dependent uptake of [¹¹C]SA4503 was measured in the brain of young (1.5 to 3 months) and aged (18 to 32 months) Wistar Hannover rats, and tracer-kinetic models were fitted to this data, using metabolite-corrected plasma radioactivity as input function.

Results

In aged animals, the injected probe was less rapidly metabolized and cleared. Logan graphical analysis and a 2-tissue compartment model (2-TCM) fit indicated changes of total distribution volume (V _T) and binding potential (BP _ND) of the tracer. BP _ND was reduced particularly in the (hypo)thalamus, pons, and medulla.

Conclusions

Some areas showed reductions of ligand binding with aging whereas binding in other areas (cortex) was not significantly affected.

     

High Impact of <Superscript>18</Superscript>F-FDG-PET on Management and Prognostic Stratification of Newly Diagnosed Small Cell Lung Cancer

Purpose

We evaluated whether ¹⁸F-FDG-PET altered stage classification, management, and prognostic stratification of newly diagnosed small cell lung cancer (SCLC).

Procedures

We identified 46 consecutive patients undergoing staging positron emission tomography for SCLC from 1993–2008 inclusive. Updated survival data from the state Cancer Registry was available on 42 of 46 patients.

Results

PET altered stage classification in 12 of 46 (26%) patients. PET altered treatment modality in nine patients, and the target mediastinal radiation field in another three patients. Therefore, PET altered management in 12 of 46 (26%) patients. Patients with limited disease (LD) on pre-PET staging had significantly longer overall survival (OS) than those upstaged to extensive disease (ED; median 18.6 months versus 5.7 months; log-rank p?versus 5.9 months; log-rank p?=?0.037).

Conclusion

PET had a major impact on stage classification, management, and prognostic stratification of newly diagnosed SCLC.

     

[<Superscript>18</Superscript>F]Fluorocholine Uptake of Parathyroid Adenoma Is Correlated with Parathyroid Hormone Level

Purpose

The aim of the study was to investigate the relationship between [¹⁸F]fluoromethyl-dimethyl-2-hydroxyethylammonium ([¹⁸F]FCh) positron emission tomography (PET) parameters, laboratory parameters, and postoperative histopathological results in patients with primary hyperparathyroidism (pHPT) due to parathyroid adenomas.

Procedures

This retrospective study was conducted in 52 patients with biochemically proven pHPT. [¹⁸F]FCh-PET parameters (maximum standardized uptake value: SUV_max) in early phase (after 2 min) and late phase (after 50 min), metabolic volume, and adenoma-to-background ratio (ABR), preoperative laboratory results (PTH and serum calcium concentration), and postoperative histopathology (location, size, volume, and weight of adenoma) were assessed. Relationship of PET parameters, laboratory parameters, and histopathological parameters was assessed using the Mann-Whitney U test and Spearman correlation coefficient. MRI characteristics of parathyroid adenomas were also analyzed.

Results

The majority of patients underwent a PET/MR scan, 42 patients (80.7 %); 10 patients (19.3 %) underwent PET/CT. We found a strong positive correlation between late-phase SUV_max and preoperative PTH level (r?=?0.768, p?<?0.001) and between late-phase ABR and preoperative PTH level (r?=?0.680, p?<?0.001). The surgical specimen volume was positively correlated with the PET/MR lesion volume (r?=?0.659, p?<?0.001). No significant association was observed between other [¹⁸F]FCh-PET parameters, laboratory parameters, and histopathological findings. Cystic adenomas were larger than non-cystic adenomas (p?=?0.048).

Conclusions

[¹⁸F]FCh uptake of parathyroid adenomas is strongly correlated with preoperative PTH serum concentration. Therefore, the preoperative PTH level might potentially be able to predict success of [¹⁸F]FCh-PET imaging in hyperparathyroidism, with higher lesion-to-background ratios being expected in patients with high PTH. PET/MR is accurate in estimating the volume of parathyroid adenomas.

     

Quantitative Analysis of [<Superscript>18</Superscript>F]FMISO PET for Tumor Hypoxia: Correlation of Modeling Results with Immunohistochemistry

Purpose

Quantitative evaluation of tumor hypoxia based on H-1-(3-[¹⁸F]fluoro-2-hydroxypropyl)-2-nitroimidazole ([¹⁸F]FMISO) positron emission tomography (PET) can deliver important information for treatment planning in radiotherapy. However, the merits and limitations of different analysis methods in revealing the underlying physiological feature are not clear. This study aimed to assess these quantitative analysis methods with the support of immunohistological data.

Procedures

Sixteen nude mice bearing xenografted human squamous cell carcinomas (FaDu or CAL-33) were scanned using 2-h dynamic [¹⁸F]FMISO PET. Tumors were resected and sliced, and the hypoxia marker pimonidazole was immunostained followed by H&E staining. The pimonidazole signal was segmented using a k-means clustering algorithm, and the hypoxic fraction (HF) was calculated as the hypoxic area/viable tumor-tissue-area ratio pooled over three tissue slices from the apical, center, and basal layers. PET images were analyzed using various methods including static analysis [standard uptake value (SUV), tumor-to-blood ratio (T/B), tumor-to-muscle ratio (T/M)] and kinetic modeling (Casciari αk _A , irreversible and reversible two-tissue compartment k ₃, Thorwarth w _A k ₃, Patlak K _i , Logan V _d , Cho K), and correlated with HF.

Results

No significant correlation was found for static analysis. A significant correlation between k ₃ of the irreversible two-tissue compartment model and HF was observed (r?=?0.61, p?=?0.01). The correlation between HF and αk _A of the Casciari model could be improved through reducing local minima by testing more sets of initial values (r?=?0.59, p?=?0.02) or by reducing the model complexity by fixing three parameters (r?=?0.63, p?=?0.0008).

Conclusions

With support of immunohistochemistry data, this study shows that various analysis methods for [¹⁸F]FMISO PET perform differently for assessment of tumor hypoxia. A better fitting quality does not necessarily mean a higher physiological correlation. Hypoxia PET analysis needs to consider both the mathematical stability and physiological fidelity. Based on the results of this study, preference should be given to the irreversible two-tissue compartment model as well as the Casciari model with reduced parameters.

     

Quantification of Tumor Hypoxic Fractions Using Positron Emission Tomography with [<Superscript>18</Superscript>F]Fluoromisonidazole ([<Superscript>18</Superscript>F]FMISO) Kinetic Analysis and Invasive Oxygen Measurements

Purpose

The purpose of this study is to use dynamic [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) positron emission tomography (PET) to compare estimates of tumor hypoxic fractions (HFs) derived by tracer kinetic modeling, tissue-to-blood ratios (TBR), and independent oxygen (pO₂) measurements.

Procedures

BALB/c mice with EMT6 subcutaneous tumors were selected for PET imaging and invasive pO₂ measurements. Data from 120-min dynamic [¹⁸F]FMISO scans were fit to two-compartment irreversible three rate constant (K ₁, k ₂, k ₃) and Patlak models (K _i). Tumor HFs were calculated and compared using K _i, k ₃, TBR, and pO₂ values. The clinical impact of each method was evaluated on [¹⁸F]FMISO scans for three non-small cell lung cancer (NSCLC) radiotherapy patients.

Results

HFs defined by TBR (≥1.2, ≥1.3, and ≥1.4) ranged from 2 to 85 % of absolute tumor volume. HFs defined by K _i (>0.004 ml min cm^?3) and k ₃ (>0.008 min^?1) varied from 9 to 85 %. HF quantification was highly dependent on metric (TBR, k ₃, or K _i) and threshold. HFs quantified on human [¹⁸F]FMISO scans varied from 38 to 67, 0 to 14, and 0.1 to 27 %, for each patient, respectively, using TBR, k ₃, and K _i metrics.

Conclusions

[¹⁸F]FMISO PET imaging metric choice and threshold impacts hypoxia quantification reliability. Our results suggest that tracer kinetic modeling has the potential to improve hypoxia quantification clinically as it may provide a stronger correlation with direct pO₂ measurements.

     

[<Superscript>11</Superscript>C]Harmine Binding to Brain Monoamine Oxidase A: Test-Retest Properties and Noninvasive Quantification

Purpose

Inhibition of the isoform A of monoamine oxidase (MAO-A), a mitochondrial enzyme catalyzing deamination of monoamine neurotransmitters, is useful in treatment of depression and anxiety disorders. [¹¹C]harmine, a MAO-A PET radioligand, has been used to study mood disorders and antidepressant treatment. However, [¹¹C]harmine binding test-retest characteristics have to date only been partially investigated. Furthermore, since MAO-A is ubiquitously expressed, no reference region is available, thus requiring arterial blood sampling during PET scanning. Here, we investigate [¹¹C]harmine binding measurements test-retest properties; assess effects of using a minimally invasive input function estimation on binding quantification and repeatability; and explore binding potentials estimation using a reference region-free approach.

Procedures

Quantification of [¹¹C]harmine distribution volume (V_T) via kinetic models and graphical analyses was compared based on absolute test-retest percent difference (TRPD), intraclass correlation coefficient (ICC), and identifiability. The optimal procedure was also used with a simultaneously estimated input function in place of the measured curve. Lastly, an approach for binding potentials quantification in absence of a reference region was evaluated.

Results

[¹¹C]harmine V_T estimates quantified using arterial blood and kinetic modeling showed average absolute TRPD values of 7.7 to 15.6 %, and ICC values between 0.56 and 0.86, across brain regions. Using simultaneous estimation (SIME) of input function resulted in V_T estimates close to those obtained using arterial input function (r?=?0.951, slope =?1.073, intercept =???1.037), with numerically but not statistically higher test-retest difference (range 16.6 to 22.0 %), but with overall poor ICC values, between 0.30 and 0.57.

Conclusions

Prospective studies using [¹¹C]harmine are possible given its test-retest repeatability when binding is quantified using arterial blood. Results with SIME of input function show potential for simplifying data acquisition by replacing arterial catheterization with one arterial blood sample at 20 min post-injection. Estimation of [¹¹C]harmine binding potentials remains a challenge that warrants further investigation.

     

Quantitative [<Superscript>18</Superscript>F]FMISO PET Imaging Shows Reduction of Hypoxia Following Trastuzumab in a Murine Model of HER2+ Breast Cancer

Purpose

Evaluation of [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO)-positron emission tomography (PET) imaging as a metric for evaluating early response to trastuzumab therapy with histological validation in a murine model of HER2+ breast cancer.

Procedures

Mice with BT474, HER2+ tumors, were imaged with [¹⁸F]FMISO-PET during trastuzumab therapy. Pimonidazole staining was used to confirm hypoxia from imaging.

Results

[¹⁸F]FMISO-PET indicated significant decreases in hypoxia beginning on day 3 (P?<?0.01) prior to changes in tumor size. These results were confirmed with pimonidazole staining on day 7 (P?<?0.01); additionally, there was a significant positive linear correlation between histology and PET imaging (r ² ?=?0.85).

Conclusions

[¹⁸F]FMISO-PET is a clinically relevant modality which provides the opportunity to (1) predict response to HER2+ therapy before changes in tumor size and (2) identify decreases in hypoxia which has the potential to guide subsequent therapy.

     

N-[<Superscript>11</Superscript>C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic Drugs

Purpose

Chemokine receptor 4 (CXCR4) is overexpressed in many cancers and a potential drug target. We have recently developed the tracer N-[¹¹C]methyl-AMD3465 for imaging of CXCR4 expression by positron emission tomography (PET). We investigated the pharmacokinetics of N-[¹¹C]methyl-AMD3465 in rats bearing a C6 tumor and assessed whether the CXCR4 occupancy by the drug Plerixafor® can be measured with this PET tracer.

Procedure

A subcutaneous C6 tumor was grown in Wistar rats. Dynamic N-[¹¹C]methyl-AMD3465 PET scans with arterial blood sampling was performed in control rats and rats pretreated with Plerixafor® (30 mg/kg, s.c). The distribution volume (V _T) of the tracer was estimated by compartment modeling with a two-tissue reversible compartment model (2TRCM) and by Logan graphical analysis. The non-displaceable binding potential (BP_ND) was estimated with the 2TRCM. Next, CXCR4 receptor occupancy of different doses of the drug Plerixafor® (0.5–60 mg/kg) was investigated.

Results

The tumor could be clearly visualized by PET in control animals. Pretreatment with 30 mg/kg Plerixafor® significantly reduced tumor uptake (SUV 0.65 ± 0.08 vs. 0.20 ± 0.01, p < 0.05). N-[¹¹C]Methyl-AMD3465 was slowly metabolized in vivo, with 70 ± 7% of the tracer in plasma still being intact after 60 min. The tracer showed reversible in vivo binding to its receptor. Both 2TRCM modeling and Logan graphical analysis could be used to estimate V _T. Pre-treatment with 30 mg/kg Plerixafor® resulted in a significant reduction in V _T (2TCRM 0.87 ± 0.10 vs. 0.23 ± 0.12, p < 0.05) and BP_ND (1.85 ± 0.14 vs. 0.87 ± 0.12, p < 0.01). Receptor occupancy by Plerixafor® was dose-dependent with an in vivo ED₅₀ of 12.7 ± 4.0 mg/kg. Logan analysis gave comparable results.

Conclusion

N-[¹¹C]Methyl-AMD3465 PET can be used to visualize CXCR4 expression and to calculate receptor occupancy. V _T determined by Logan graphical analysis is a suitable parameter to assess CXCR4 receptor occupancy. This approach can easily be translated to humans and used for early drug development and optimization of drug dosing schedules.

     

Uptake of Radium-223 Dichloride and Early [<Superscript>18</Superscript>F]NaF PET Response Are Driven by Baseline [<Superscript>18</Superscript>F]NaF Parameters: a Pilot Study in Castration-Resistant Prostate Cancer Patients

Purpose

The purpose of this study is to identify predictive factors on baseline [¹⁸F]NaF positron emission tomography (PET)/computed tomography (CT) of early response to radium-223 dichloride after 3 cycles of treatment in metastatic castration-resistant prostate cancer patients.

Procedures

Analysis of 152 metastases was performed in six consecutive patients who underwent [¹⁸F]NaF PET/CT at baseline and for early monitoring after 3 cycles of radium-223 dichloride. All metastases depicted on whole-body [¹⁸F]NaF PET/CT were contoured and CT (density in Hounsfield units, sclerotic, mixed, or lytic appearance) as well as [¹⁸F]NaF [maximum standardized uptake value (SUV_max), SUV_mean, and lesion volume (V_18F-NaF)] patterns were recorded. Tumor response was defined as percentage change in SUV_max and SUV_mean between baseline and post-treatment PET. Bone lesions were defined as stable, responsive, or progressive, according to thresholds derived from a recent multicentre test-retest study in [¹⁸F]NaF PET/CT. Total [¹⁸F]NaF uptake in metastases, defined as MATV × SUV_mean, was correlated to uptake of radium-223 on biodistribution scintigraphy performed 7 days after the first cycle of treatment.

Results

Among metastases, 116 involved the axial skeleton and 36 the appendicular skeleton. Lesions were sclerotic in 126 cases and mixed in 26 cases. No lytic lesion was depicted. ROC analysis showed that SUV_max and SUV_mean were better predictors of lesion response than V_18F-NaF and density on CT (P < 0.0001 and P = 0.001, respectively). SUV_max and SUV_mean were predictors of individual tumor response in separate multivariate models (P = 0.01 and P = 0.02, respectively). CT pattern (mixed versus sclerotic) and lesion density were independent predictors only when assessing response with delta SUV_max (P = 0.002 and 0.007, respectively). A good correlation between total [¹⁸F]NaF uptake within metastases and their relative radium-223 uptake assessed by two observers 7 days after treatment (r = 0.72 and 0.77, P < 0.0001) was found.

Conclusions

SUV_max and SUV_mean on baseline [¹⁸F]NaF PET/CT are independent predictors of bone lesions’ response to 3 cycles of radium-223 dichloride, supporting the use of NaF to select patients more likely to respond to treatment.

     

Parametric Imaging of [<Superscript>11</Superscript>C]Flumazenil Binding in the Rat Brain

Purpose

This study evaluates the performance of several parametric methods for assessing [¹¹C]flumazenil binding distribution in the rat brain.

Procedures

Dynamic (60 min) positron emission tomography data with metabolite-corrected plasma input function were retrospectively analyzed (male Wistar rats, n = 10). Distribution volume (V _T) images were generated from basis function method (BFM), Logan graphical analysis (Logan), and spectral analysis (SA). Using the pons as pseudo-reference tissue, binding potential (BP _ND and DVR–1) images were obtained from receptor parametric imaging algorithms (RPM and SRTM2) and reference Logan (RLogan). Standardized uptake value images (SUV and SUVR) were also computed for different intervals post-injection. Next, regional averages were extracted from the parametric images, using pre-defined volumes of interest, which were also applied to the regional time-activity curves from the dynamic data. Parametric data were compared to their regional counterparts and to two-tissue compartment model (2TCM)-based values (previously defined as the model of choice for rats). Parameter agreement was assessed by linear regression analysis and Bland-Altman plots.

Results

All parametric methods strongly correlated to their regional counterparts (R ² > 0.97) and to the 2TCM values (R ² ≥ 0.95). SA and RLogan underestimated V _T and BP _ND (slope of 0.93 and 0.86, respectively), while SUVR-1 overestimated BP _ND (slope higher than 1.07 for all intervals). While BFM and SRTM2 had the smallest bias to 2TCM values (0.05 for both), ratio Bland-Altman plots showed Logan and RLogan displayed relative errors which were comparable between different regions, in contrast with the other methods. Although SUV consistently underestimated V _T, the bias in this method was also constant across regions.

Conclusions

All parametric methods performed well for the analysis of [¹¹C]flumazenil distribution and binding in the rat brain. However, Logan and RLogan slightly outperformed the other methods in terms of precision, providing robust parameter estimation and constant bias. Yet, other methods can be of interest, because they can provide tissue perfusion (i.e., K ₁ with BFM and SA), relative flow (i.e., R ₁ with RPM and SRTM2), and model order (SA) images.

     

Evaluation of Pancreatic VMAT2 Binding with Active and Inactive Enantiomers of [<Superscript>18</Superscript>F]FP-DTBZ in Healthy Subjects and Patients with Type 1 Diabetes

Purpose

Previous studies demonstrated the utility of [¹⁸F]fluoropropyl-(+)-dihydrotetrabenazine ([¹⁸F]FP-(+)-DTBZ) as a positron emission tomography (PET) radiotracer for the vesicular monoamine transporter type 2 (VMAT2) to quantify beta cell mass in healthy control (HC) and type 1 diabetes mellitus (T1DM) groups. Quantification of specific binding requires measurement of non-displaceable uptake. Our goal was to identify a reference tissue (renal cortex or spleen) to quantify pancreatic non-specific binding of [¹⁸F]FP-(+)-DTBZ with the inactive enantiomer, [¹⁸F]FP-(?)-DTBZ. This was the first human study of [¹⁸F]FP-(?)-DTBZ.

Procedures

Six HCs and four T1DM patients were scanned on separate days after injection of [¹⁸F]FP-(+)-DTBZ or [¹⁸F]FP-(?)-DTBZ. Distribution volumes (V_T) and standardized uptake values (SUVs) were compared between groups. Three methods for calculation of non-displaceable uptake (V_ND) or reference SUV were applied: (1) use of [¹⁸F]FP-(+)-DTBZ reference V_T as V_ND, assuming V_ND is uniform across organs; (2) use of [¹⁸F]FP-(?)-DTBZ pancreatic V_T as V_ND, assuming that V_ND is uniform between enantiomers in the pancreas; and (3) use of a scaled [¹⁸F]FP-(+)-DTBZ reference V_T as V_ND, assuming that a ratio of non-displaceable uptake between organs is uniform between enantiomers. Group differences in V_T (or SUV), binding potential (BP_ND), or SUV ratio (SUVR) were estimated using these three methods.

Results

[¹⁸F]FP-(?)-DTBZ V_T values were different among organs, and V_T(+) and V_T(?) were also different in the renal cortex and spleen. Method 3 with the spleen to estimate V_ND (or reference SUV) gave the highest non-displaceable uptake and the largest HC vs. T1DM group differences. Significant group differences were also observed in V_T (or SUV) with method 1 using spleen. SUV was affected by differences in the input function between groups and between enantiomers.

Conclusions

Non-displaceable uptake was different among organs and between enantiomers. Use of scaled spleen V_T values for V_ND is a suitable method for quantification of VMAT2 in the pancreas.

     

Preclinical Characterization of the Phosphodiesterase 10A PET Tracer [<Superscript>11</Superscript>C]MK-8193

Purpose

A positron emission tomography (PET) tracer for the enzyme phosphodiesterase 10A (PDE10A) is desirable to guide the discovery and development of PDE10A inhibitors as potential therapeutics. The preclinical characterization of the PDE10A PET tracer [¹¹C]MK-8193 is described.

Procedures

In vitro binding studies with [³H]MK-8193 were conducted in rat, monkey, and human brain tissue. PET studies with [¹¹C]MK-8193 were conducted in rats and rhesus monkeys at baseline and following administration of a PDE10A inhibitor.

Results

[³H]MK-8193 is a high-affinity, selective PDE10A radioligand in rat, monkey, and human brain tissue. In vivo, [¹¹C]MK-8193 displays rapid kinetics, low test-retest variability, and a large specific signal that is displaced by a structurally diverse PDE10A inhibitor, enabling the determination of pharmacokinetic/enzyme occupancy relationships.

Conclusions

[¹¹C]MK-8193 is a useful PET tracer for the preclinical characterization of PDE10A therapeutic candidates in rat and monkey. Further evaluation of [¹¹C]MK-8193 in humans is warranted.

     

Preclinical Evaluation of [<Superscript>18</Superscript>F]THK-5105 Enantiomers: Effects of Chirality on Its Effectiveness as a Tau Imaging Radiotracer

Purpose

Noninvasive imaging of tau and amyloid-β pathologies would facilitate diagnosis of Alzheimer’s disease (AD). Recently, we have developed [¹⁸F]THK-5105 for selective detection of tau pathology by positron emission tomography (PET). The purpose of this study was to clarify biological properties of optically pure [¹⁸F]THK-5105 enantiomers.

Procedures

Binding for tau aggregates in AD brain section was evaluated by autoradiography (ARG). In vitro binding assays were performed to evaluate the binding properties of enantiomers for AD brain homogenates. The pharmacokinetics in the normal mouse brains was assessed by ex vivo biodistribution assay

Results

The ARG of enantiomers showed the high accumulation of radioactivity corresponding to the distribution of tau deposits. In vitro binding assays revealed that (S)-[¹⁸F]THK-5105 has slower dissociation from tau than (R)-[¹⁸F]THK-5105. Biodistribution assays indicated that (S)-[¹⁸F]THK-5105 eliminated faster from the mouse brains and blood compared with (R)-[¹⁸F]THK-5105.

Conclusion

(S)-[¹⁸F]THK-5105 could be more suitable than (R)-enantiomer for a tau imaging agent.

     

[<Superscript>11</Superscript>C]acetate PET Imaging is not Always Associated with Increased Lipogenesis in Hepatocellular Carcinoma in Mice

Purpose

Altered metabolism, including increased glycolysis and de novo lipogenesis, is one of the hallmarks of cancer. Radiolabeled nutrients, including glucose and acetate, are extensively used for the detection of various tumors, including hepatocellular carcinomas (HCCs). High signal of [¹¹C]acetate positron emission tomography (PET) in tumors is often considered to be associated with increased expression of fatty acid synthase (FASN) and increased de novo lipogenesis in tumor tissues. Defining a subset of tumors with increased [¹¹C]acetate PET signal and thus increased lipogenesis was suggested to help select a group of patients, who may benefit from lipogenesis-targeting therapies.

Procedures

To investigate whether [¹¹C]acetate PET imaging is truly associated with increased de novo lipogenesis along with hepatocarcinogenesis, we performed [¹¹C]acetate PET imaging in wild-type mice as well as two mouse HCC models, induced by myrAKT/Ras^V12 (AKT/Ras) and PIK3CA^1047R/c-Met (PI3K/Met) oncogene combinations. In addition, we analyzed FASN expression and de novo lipogenesis rate in these mouse liver tissues.

Results

We found that while HCCs induced by AKT/Ras co-expression showed high levels of [¹¹C]acetate PET signal compared to normal liver, HCCs induced by PI3K/Met overexpression did not. Intriguingly, elevated FASN expression and increased de novo lipogenesis rate were observed in both AKT/Ras and PI3K/Met HCCs.

Conclusion

Altogether, our study suggests that [¹¹C]acetate PET imaging can be a useful tool for imaging of a subset of HCCs. However, at molecular level, the increased [¹¹C]acetate PET imaging is not always associated with increased FASN expression or de novo lipogenesis.

     

Evaluation of TSPO PET Ligands [<Superscript>18</Superscript>F]VUIIS1009A and [<Superscript>18</Superscript>F]VUIIS1009B: Tracers for Cancer Imaging

Purpose

Positron emission tomography (PET) ligands targeting translocator protein (TSPO) are potential imaging diagnostics of cancer. In this study, we report two novel, high-affinity TSPO PET ligands that are 5,7 regioisomers, [¹⁸F]VUIIS1009A ([¹⁸F]3A) and [¹⁸F]VUIIS1009B ([¹⁸F]3B), and their initial in vitro and in vivo evaluation in healthy mice and glioma-bearing rats.

Procedures

VUIIS1009A/B was synthesized and confirmed by X-ray crystallography. Interactions between TSPO binding pocket and novel ligands were evaluated and compared with contemporary TSPO ligands using 2D ¹H-¹⁵N heteronuclear single quantum coherence (HSQC) spectroscopy. In vivo biodistribution of [¹⁸F]VUIIS1009A and [¹⁸F]VUIIS1009B was carried out in healthy mice with and without radioligand displacement. Dynamic PET imaging data were acquired simultaneously with [¹⁸F]VUIIS1009A/B injections in glioma-bearing rats, with binding reversibility and specificity evaluated by radioligand displacement. In vivo radiometabolite analysis was performed using radio-TLC, and quantitative analysis of PET data was performed using metabolite-corrected arterial input functions. Imaging was validated with histology and immunohistochemistry.

Results

Both VUIIS1009A (3A) and VUIIS1009B (3B) were found to exhibit exceptional binding affinity to TSPO, with observed IC₅₀ values against PK11195 approximately 500-fold lower than DPA-714. However, HSQC NMR suggested that VUIIS1009A and VUIIS1009B share a common binding pocket within mammalian TSPO (mTSPO) as DPA-714 and to a lesser extent, PK11195. [¹⁸F]VUIIS1009A ([¹⁸F]3A) and [¹⁸F]VUIIS1009B ([¹⁸F]3B) exhibited similar biodistribution in healthy mice. In rats bearing C6 gliomas, both [¹⁸F]VUIIS1009A and [¹⁸F]VUIIS1009B exhibited greater binding potential (k ₃/k ₄)in tumor tissue compared to [¹⁸F]DPA-714. Interestingly, [¹⁸F]VUIIS1009B exhibited significantly greater tumor uptake (V _T) than [¹⁸F]VUIIS1009A, which was attributed primarily to greater plasma-to-tumor extraction efficiency.

Conclusions

The novel PET ligand [¹⁸F]VUIIS1009B exhibits promising characteristics for imaging glioma; its superiority over [¹⁸F]VUIIS1009A, a regioisomer, appears to be primarily due to improved plasma extraction efficiency. Continued evaluation of [¹⁸F]VUIIS1009B as a high-affinity TSPO PET ligand for precision medicine appears warranted.

     

Preclinical Evaluation of 4-[<Superscript>18</Superscript>F]Fluoroglutamine PET to Assess ASCT2 Expression in Lung Cancer

Purpose

Alanine-serine-cysteine transporter 2 (ASCT2) expression has been demonstrated as a promising lung cancer biomarker. (2S,4R)-4-[¹⁸F]Fluoroglutamine (4-[¹⁸F]fluoro-Gln) positron emission tomography (PET) was evaluated in preclinical models of non-small cell lung cancer as a quantitative, non-invasive measure of ASCT2 expression.

Procedures

In vivo microPET studies of 4-[¹⁸F]fluoro-Gln uptake were undertaken in human cell line xenograft tumor-bearing mice of varying ASCT2 levels, followed by a genetically engineered mouse model of epidermal growth factor receptor (EGFR)-mutant lung cancer. The relationship between a tracer accumulation and ASCT2 levels in tumors was evaluated by IHC and immunoblotting.

Result

4-[¹⁸F]Fluoro-Gln uptake, but not 2-deoxy-2-[¹⁸F]fluoro-D-glucose, correlated with relative ASCT2 levels in xenograft tumors. In genetically engineered mice, 4-[¹⁸F]fluoro-Gln accumulation was significantly elevated in lung tumors, relative to normal lung and cardiac tissues.

Conclusions

4-[¹⁸F]Fluoro-Gln PET appears to provide a non-invasive measure of ASCT2 expression. Given the potential of ASCT2 as a lung cancer biomarker, this and other tracers reflecting ASCT2 levels could emerge as precision imaging diagnostics in this setting.

     

Quantification of Tau Load Using [<Superscript>18</Superscript>F]AV1451 PET

Purpose

The tau tracer [¹⁸F]AV1451, also known as flortaucipir, is a promising ligand for imaging tau accumulation in Alzheimer’s disease (AD). Most of the previous studies have quantified tau load using standardized uptake value ratios (SUVr) derived from a static [¹⁸F]AV1451 scan. SUVr may, however, be flow dependent and, especially for longitudinal studies, should be validated against a fully quantitative approach. The objective of this study was to identify the optimal tracer kinetic model for measuring tau load using [¹⁸F]AV1451.

Procedures

Following intravenous injection of 225 ± 16 MBq [¹⁸F]AV1451, 130 min dynamic PET scans were performed in five biomarker confirmed AD patients and five controls. Arterial blood sampling was performed to obtain a metabolite-corrected plasma input function. Next, regional time–activity curves were generated using PVElab software. These curves were analysed using several pharmacokinetic models.

Results

The reversible single tissue compartment model (1T2k_V_B) was the preferred model for all but one control. For AD patients, however, model preference shifted towards a reversible two tissue compartmental model (2T4k_V_B). The simplified reference tissue model (SRTM) derived binding potential (BP_ND) showed good correlation (AD: r ² = 0.87, slope = 1.06; controls: r ² = 0.87, slope = 0.86) with indirect plasma input binding (distribution volume ratio-1). Standardized uptake value ratios (80–100 min) correlated well with DVR (r ² = 0.93, slope = 1.07) and SRTM-derived BP_ND (r ² = 0.84, slope = 0.95). In addition, regional differences in tracer binding between subject groups in different tau-specific regions were observed.

Conclusions

Model preference of [¹⁸F]AV1451 appears to depend on subject status and, in particular, V_T. The relationship between model preference and V_T suggests that (higher) tau load may be reflected by a second tissue compartment. Nevertheless, consistent results can be obtained using a 2T4k_V_B model. In addition, SRTM can be used to derive BP_ND.