Efficacy benefit of an NK<Subscript>1</Subscript> receptor antagonist (NK<Subscript>1</Subscript>RA) in patients receiving carboplatin: supportive evidence with NEPA (a fixed combination of the NK<Subscript>1</Subscript> RA,netupitant, and palonosetron) and aprepitant regimens

Purpose

Antiemetic guideline recommendations are inconsistent as to whether a neurokinin-1 receptor antagonist (NK₁ RA) should be administered with a 5-hydroxytryptamine-3 (5HT₃) RA + dexamethasone (DEX) in patients receiving carboplatin. Patients receiving cisplatin routinely receive an NK₁ RA-containing regimen with a resulting 14–22 % benefit in no emesis rates over a 5-HT₃ RA/DEX control. Recent studies suggest a similar benefit in patients receiving carboplatin. NEPA is the first fixed antiemetic combination agent and comprises the highly selective NK₁ RA, netupitant, and pharmacologically distinct 5-HT₃ RA, palonosetron (PALO). This paper presents the efficacy of NEPA in the subset of patients receiving carboplatin in a phase 3 trial (NCT01376297), in the context of aprepitant (APR) data in the carboplatin setting.

Methods

One hundred ninety-six patients (47 % of all study patients: n = 145 NEPA + DEX; n = 51 APR + PALO + DEX) received carboplatin in a multinational, double-blind, randomized phase 3 study. Complete response (CR: no emesis/rescue) and no significant nausea (NSN: score ≤25 on 100 mm visual analog scale) rates were calculated.

Results

Cycle 1–4 overall (0–120 h) CR rates were similar for NEPA (80, 91, 92, and 93 %) and APR (82, 88, 88, and 90 %). Overall NSN rates were also similar (NEPA 84–96 %; APR 82–90 %).

Conclusions

Response rates for NEPA and APR regimens were similar and consistent with prior studies evaluating the contribution of adding NK₁ RAs in patients receiving carboplatin. Considering such evidence, guideline groups/practitioners should consider giving a NK₁ RA antiemetic triplet in patients receiving carboplatin.

     

Investigation of the Brain Biodistribution of the Lipoprotein-Associated Phospholipase A<Subscript>2</Subscript> (Lp-PLA<Subscript>2</Subscript>) Inhibitor [<Superscript>18</Superscript>F]GSK2647544 in Healthy Male Subjects

Purpose

GSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A₂ (Lp-PLA₂), which was in development as a potential treatment for Alzheimer’s disease (AD). In order to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhibitor, [¹⁸F]GSK2647544, was manufactured for use in a positron emission tomography (PET) biodistribution study.

Procedures

[¹⁸F]GSK2647544 was produced using a novel, copper iodide (Cu(I)) mediated, [¹⁸F]trifluoromethylation methodology. Healthy male subjects (n?=?4, age range 34–42) received an oral dose of unlabelled GSK2647544 (100 mg) and after 2 h an intravenous (iv) injection of [¹⁸F]GSK2647544 (average injected activity and mass were 106?±?47 MBq and 179?±?55 μg, respectively) followed by dynamic PET scans for 120 min. Defined regions of interest (ROI) throughout the brain were used to obtain regional time-activity curves (TACs) and compartmental modelling analysis used to estimate the primary outcome measure, whole brain volume of distribution (V_T). Secondary PK and safety endpoints were also recorded.

Results

PET dynamic data were successfully obtained from all four subjects and there were no clinically significant variations of the safety endpoints. Inspection of the TACs indicated a relatively homogenous uptake of [¹⁸F]GSK2647544 across all the ROIs examined. The mean whole brain V_T was 0.56 (95 % CI, 0.41–0.72). Secondary PK parameters, C_max (geometric mean) and T_max (median), were 354 ng/ml and 1.4 h, respectively. Metabolism of GSK2647544 was relatively consistent across subjects, with 20–40 % of the parent compound [¹⁸F]GSK2647544 present after 120 min.

Conclusions

The study provides evidence that GSK2647544 is able to cross the blood brain barrier in healthy male subjects leading to a measurable brain exposure. The administered doses of GSK2647544 were well tolerated. Exploratory modelling suggested that a twice-daily dose of 102 mg, at steady state, would provide ~80 % trough inhibition of brain Lp-PLA₂ activity.

Trial Registration

Clintrials.gov: NCT01924858.

     

Stability of liver proton density fat fraction and changes in <Emphasis Type="Italic">R</Emphasis><Subscript>2</Subscript>* measurements induced by administering gadoxetic acid at 3T MRI

Objective

To assess changes in liver proton density fat fraction (PDFF) and R ₂* measurements in the presence of changes in tissue relaxation rates induced by administrating gadoxetic acid, using two different image reconstruction methods at 3T MRI.

Methods

Forty-five patients were imaged at 3T with chemical-shift-based MRI sequences before and 20 min after administration of gadoxetic acid. Image reconstructions were performed using hybrid and complex methods to obtain PDFF and R ₂* images. A single radiologist measured PDFF and R ₂* values on precontrast and postcontrast images. Precontrast and postcontrast PDFF values were compared using intraclass correlation coefficient (ICC), linear regression, and Bland–Altman analysis. Changes in R ₂* values from precontrast to postcontrast were correlated with relative liver enhancement (RLE) based on signal intensities on T ₁-weighted images using Spearman’s rank correlation.

Results

PDFF values were similar between precontrast and postcontrast images (ICC = 0.99, linear regression slopes = 0.98, mean difference = ?0.21 to ?0.31%). PDFF measurements were stable between precontrast and postcontrast images. Changes in R ₂* values were correlated with RLE (p < 0.001, r = 0.49–0.71).

Conclusions

PDFF measurements from both image reconstruction methods are stable in the presence of changes in tissue relaxation rates after administering gadoxetic acid at 3T MRI. Changes in R ₂* values correlate with established measures of gadoxetic acid uptake based on T ₁-weighted images.

     

Optimization of a Labeling and Kit Preparation Method for Ga-68 Labeled DOTATATE,Using Cation Exchange Resin Purified Ga-68 Eluates Obtained from a Tin Dioxide <Superscript>68</Superscript>Ge/<Superscript>68</Superscript>Ga Generator

Purpose

The aim of this study was to optimize a radiolabeling method using cationic processed Ga-68 eluates from a SnO₂-based ⁶⁸Ge/⁶⁸Ga generator, followed by the development of DOTA-Tyr³-Thre⁸-octreotide (DOTATATE) kits.

Procedures

Diluted generator eluates were adsorbed on a SCX resin and desorbed with acidified 5 M NaCl solution. Optimized labeling conditions were determined by variation of pH, using 35 μg DOTATATE and sodium acetate buffer. DOTATATE kits were developed based on optimized radiolabeling conditions, were labeled, and evaluated.

Results

Optimized labeling conditions resulted in a radiolabeling efficiency of around 99 % and radiochemical yield of almost 85 %. Different kit preparation methods did not significantly influence the radiolabeling results. Kits were found to be stable over 3 months.

Conclusion

A labeling method using SCX-processed Ga-68 eluates was optimized. DOTATATE kits specifically for these SCX-processed Ga-68 eluates were successfully formulated. A post-labeling Sep-Pak C18 purification should be optional.

     

Development and Evaluation of User-Friendly Single Vial DOTA-Peptide Kit Formulations,Specifically Designed for Radiolabelling with <Superscript>68</Superscript>Ga from a Tin Dioxide <Superscript>68</Superscript>Ge/<Superscript>68</Superscript>Ga Generator

Purpose

This study was aimed to develop single vial 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-peptide kits to be used with fractionated eluates from a SnO₂-based ⁶⁸Ge/⁶⁸Ga generator.

Procedures

Kits were formulated with 35 μg DOTA-Tyr³-Thre⁸-octreotide, DOTA-[Tyr³]-octreotide and DOTA-[NaI³]-octreotide (DOTATATE, DOTATOC and DOTANOC) and sodium acetate powder, vacuum-dried and stored at ?20 °C for up to 12 months. Labelling of the kits was carried out with 2 ml ⁶⁸Ga eluate. Comparative labelling was carried out using aqueous DOTA-peptide stock solutions kept frozen at ?20 °C for up to 12 months.

Results

The quality of the kits was found to be suitable over a 1-year storage period (pH, sterility, endotoxin content, radiolabelling efficiency and radiochemical yields of ⁶⁸Ga-labelled DOTA-peptides). Radiochemical yields ranged from 73 to 83 %, while those obtained from stock solutions from 64 to 79 %. No significant decline in kit labelling yields was observed over a 12-month storage period.

Conclusion

The single vial kit formulations met the quality release specifications for human administration and appear to be highly advantageous over using peptide stock solutions in terms of stability and user-friendliness.

     

Biodistribution and Radiation Dosimetry of [<Superscript>18</Superscript>F]Mefway in Humans

Purpose

[¹⁸F]Mefway is a positron emission tomography (PET) radioligand for quantification of the brain serotonin 1A (5-HT_1A) receptor density. The purpose of this study was to evaluate the radiation safety of [¹⁸F]Mefway in humans.

Procedures

Six healthy volunteers (three males and three females) were whole-body PET scanned for 114 min after injection of [¹⁸F]Mefway (226?±?35 MBq). Estimated radiation doses were determined by the OLINDA/EXM software.

Results

[¹⁸F]Mefway was safe and well tolerated by all subjects. Residence time ranges from 0 (gallbladder) to 0.822 h (urinary bladder wall). While the estimated radiation doses in the reproductive and blood-forming organs were below 13.35–22.87 μSv/MBq, radiation dose in the urinary bladder wall was 471 μSv/MBq. The mean effective dose was 40.23?±?6.63 μSv/MBq.

Conclusion

For a typical single injection of 185 MBq (5 mCi), the dose will result in 87.1 mSv for the urinary bladder wall. To reduce radiation burden, the bladder voiding can be used before [¹⁸F]Mefway PET scan.

     

Effects of Long-Term Caffeine Consumption on the Adenosine A<Subscript>1</Subscript> Receptor in the Rat Brain: an <Emphasis Type="Italic">In Vivo</Emphasis> PET Study with [<Superscript>18</Superscript>F]CPFPX

Purpose

Caffeine, a nonselective antagonist of adenosine receptors, is the most popular psychostimulant worldwide. Recently, a protective role of moderate chronic caffeine consumption against neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease has been discussed. Thus, aim of the present study was an in vivo investigation of effects of long-term caffeine consumption on the adenosine A₁ receptor (A₁AR) in the rat brain.

Procedures

Sixteen adult, male rats underwent five positron emission tomography (PET) scans with the highly selective A₁AR radioligand [¹⁸F]CPFPX in order to determine A₁AR availability. After the first baseline PET scan, the animals were assigned to two groups: Caffeine treatment and control group. The caffeine-treated animals received caffeinated tap water (30 mg/kg bodyweight/day, corresponding to 4–5 cups of coffee per day in humans) for 12 weeks. Subsequently, caffeine was withdrawn and repeated PET measurements were performed on day 1, 2, 4, and 7 of caffeine withdrawal. The control animals were measured according to the same time schedule.

Results

At day 1, after 4.4 h of caffeine withdrawal, a significant decrease (? 34.5%, p < 0.001) of whole brain A₁AR availability was observed. Unlike all other investigated brain regions in caffeine-treated rats, the hypothalamus and nucleus accumbens showed no significant intraindividual differences between baseline and first withdrawal PET scan. After approximately 27 h of caffeine withdrawal, the region- and group-specific effects disappeared and A₁AR availability settled around baseline.

Conclusions

The present study provides evidence that chronic caffeine consumption does not lead to persistent changes in functional availability of cerebral A₁ARs which have previously been associated with neuroprotective effects of caffeine. The acute and region-specific decrease in cerebral A₁AR availability directly after caffeine withdrawal is most likely caused by residual amounts of caffeine metabolites disguising an unchanged A₁AR expression at this early time-point.

     

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.

     

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.

     

Human Radiation Dosimetry of [<Superscript>18</Superscript>F]AV-1451(T807) to Detect Tau Pathology

Purpose

[¹⁸F]AV-1451 is a positron emission tomography (PET) radioligand for detecting paired helical filament tau. Our aim was to estimate the radiation dose of [¹⁸F]AV-1451 in humans.

Procedures

Whole-body PET scans were acquired for six healthy volunteers (three male, three female) for 128 min after injection of [¹⁸F]AV-1451 (268?±?31 MBq). Radiation doses were estimated using the OLINDA/EXM software.

Results

The estimated organ doses ranged from 7.81 to 81.2 μSv/MBq. The critical organ for radiation burden was the liver. Radiation doses to the reproductive and blood-forming organs were 14.15, 8.43, and 18.35 μSv/MBq for the ovaries, testes, and red marrow, respectively. The mean effective dose was 22.47?±?3.59 μSv/MBq.

Conclusions

A standard single injection of 185 MBq (5 mCi) results in an effective dose of 4.7 mSv in a healthy subject. Therefore, [¹⁸F]AV-1451 could be used in multiple PET scans of the same subject per year.

     

<Emphasis Type="Italic">L</Emphasis><Subscript><Emphasis Type="Italic">p</Emphasis></Subscript> Regularization for Bioluminescence Tomography Based on the Split Bregman Method

Purpose

Bioluminescence tomography (BLT) is a promising in vivo optical imaging technique in preclinical research at cellular and molecular levels. The problem of BLT reconstruction is quite ill-posed and ill-conditioned. In order to achieve high accuracy and efficiency for its inverse reconstruction, we proposed a novel approach based on L _p regularization with the Split Bregman method.

Procedures

The diffusion equation was used as the forward model. Then, we defined the objective function of L _p regularization and developed a Split Bregman iteration algorithm to optimize this function. After that, we conducted numerical simulations and in vivo experiments to evaluate the accuracy and efficiency of the proposed method.

Results

The results of the simulations indicated that compared with the conjugate gradient and iterative shrinkage methods, the proposed method is more accurate and faster for multisource reconstructions. Furthermore, in vivo imaging suggested that it could clearly distinguish the viable and apoptotic tumor regions.

Conclusions

The Split Bregman iteration method is able to minimize the L _p regularization problem and achieve fast and accurate reconstruction in BLT.

     

Comparison of clinical MRI liver iron content measurements using signal intensity ratios, <Emphasis Type="Italic">R</Emphasis><Subscript>2</Subscript> and <Emphasis Type="Italic">R</Emphasis><Subscript>2</Subscript>*

Purpose

To compare three types of MRI liver iron content (LIC) measurement performed in daily clinical routine in a single center over a 6-year period.

Methods

Patients undergoing LIC MRI-scans (1.5T) at our center between January 1, 2008 and December 31, 2013 were retrospectively included. LIC was measured routinely with signal intensity ratio (SIR) and MR-relaxometry (R ₂ and R ₂*) methods. Three observers placed regions-of-interest. The success rate was the number of correctly acquired scans over the total number of scans. Interobserver agreement was assessed with intraclass correlation coefficients (ICC) and Bland–Altman analysis, correlations between LIC_SIR, R ₂, R ₂*, and serum values with Spearman’s rank correlation coefficient. Diagnostic accuracies of LIC_SIR, R ₂ and serum transferrin, transferrin-saturation, and ferritin compared to increased R ₂* (≥44 Hz) as indicator of iron overload were assessed using ROC-analysis.

Results

LIC MRI-scans were performed in 114 subjects. SIR, R ₂, and R ₂* data were successfully acquired in 102/114 (89%), 71/114 (62%), and 112/114 (98%) measurements, with the lowest success rate for R ₂. The ICCs of SIR, R ₂, and R ₂* did not differ at 0.998, 0.997, and 0.999. R ₂ and serum ferritin had the highest diagnostic accuracies to detect elevated R ₂* as mark of iron overload.

Conclusions

SIR and R ₂* are preferable over R ₂ in terms of success rates. R ₂*’s shorter acquisition time and wide range of measurable LIC values favor R ₂* over SIR for MRI-based LIC measurement.

     

Radiation Dosimetry of a Novel Adenosine A<Subscript>2A</Subscript> Receptor Radioligand [<Superscript>11</Superscript>C]Preladenant Based on PET/CT Imaging and Ex Vivo Biodistribution in Rats

Purpose

[¹¹C]Preladenant was developed as a novel adenosine A_2A receptor PET radioligand. The aim of this study was to determine the radiation dosimetry of [¹¹C]preladenant and to investigate whether dosimetry estimation based on organ harvesting can be replaced by positron emission tomography (PET)/x-ray computed tomography (CT) imaging in rats.

Procedures

Male Wistar rats (n?=?35) were i.v. injected with [¹¹C]preladenant. The tracer biodistribution was determined by organ harvesting at 1, 5, 15, 30, 60, and 90 min post injection. Hollow organs including the stomach, intestines, and urinary bladder were harvested with contents. In 10 rats, a 90-min dynamic PET/CT scan of the torso was acquired. Twenty volumes of interest (VOIs) were manually drawn on the PET image using the CT image of the same animal as anatomical reference. The dynamic time-activity curves were used to calculate organ residence times (RTs). Human radiation dosimetry estimates, derived from rat data, were calculated with OLINDA/EXM 1.1.

Results

PET-imaging and organ-harvesting estimated comparable organ RTs, with differences of 6–27 %, except for the lungs, pancreas, and urinary bladder, with differences of 48, 53, and 60, respectively. The critical organ was the small intestine with a dose of 25 μSv/MBq. The effective doses (EDs) calculated from imaging-based and organ-harvesting-derived data were 5.5 and 5.6 μSv/MBq, respectively, using the International Commission on Radiological Protection 60 tissue weighting factors.

Conclusions

The ED of [¹¹C]preladenant (2 mSv for a 370-MBq injected dose) is comparable with other C-11-labeled PET tracers. Estimation of the radiation dosimetry of [¹¹C]preladenant by PET/CT imaging in rats is feasible and gives comparable results to organ harvesting, provided that small VOIs are used and the content of hollow organs is taken into account. Dosimetry by PET imaging can strongly reduce the number of laboratory animals required.

     

MAO-B Inhibitors Do Not Block <Emphasis Type="Italic">In Vivo</Emphasis> Flortaucipir([<Superscript>18</Superscript>F]-AV-1451) Binding

Purpose

Recent evidence suggests that the tau radiotracer [¹⁸F]THK-5351 displays high affinity for the monoamine oxidase type B (MAO-B) enzyme. Utilizing another tau-tracer, flortaucipir ([¹⁸F]AV-1451), we previously reported that non-demented Parkinson’s disease patients show off-target binding in subcortical structures, but no appreciable cortical uptake. However, 59 % of these patients were receiving MAO-B inhibitors at the time of their scan. Here, we retrospectively investigated if MAO-B inhibitors in clinical doses affect flortaucipir binding.

Procedures

We compared the standard uptake values of flortaucipir at regional and voxel levels in Parkinson’s disease patients who received MAO-B inhibitors with those who did not.

Results

Sixteen of 27 Parkinson’s disease patients received MAO-B inhibitors at the time of scan. We found no significant flortaucipir uptake differences between the groups at voxel or regional levels.

Conclusion

Use of MAO-B inhibitors at pharmaceutical levels did not significantly affect flortaucipir binding. Thus, MAO-B does not appear to be a significant binding target of flortaucipir.

     

Novel Approach to Repeated Arterial Blood Sampling in Small Animal PET: Application in a Test-Retest Study with the Adenosine A1 Receptor Ligand [<Superscript>11</Superscript>C]MPDX

Purpose

Small animal positron emission tomography (PET) can be used to detect small changes in neuroreceptor availability. This often requires rapid arterial blood sampling. However, current catheterization procedures do not allow repeated blood sampling. We have developed a procedure which allows arterial sampling on repeated occasions in the same animal.

Procedures

Eleven male Wistar rats were two times catheterized via a superficial branch of a femoral artery and scanned with [¹¹C]MPDX and blood sampling. PET images were co-registered to a magnetic resonance imaging (MRI) template. Regional tracer distribution volumes (V _T) in the brain were calculated by the Logan analysis. The procedure was repeated after 1 week.

Results

Surgery was successful in 90 % of the cases, and discomfort was minor. The V _T data showed small differences between test and retest, low between subject variability, and a strong agreement between and within subjects.

Conclusion

Repeated quantitative imaging with a high reproducibility is possible with this approach.

     

Measurement of sound pressure and temperature in tissue-mimicking material using an optical fiber Bragg grating sensor

Purpose

The experimental investigation of an optical fiber Bragg grating (FBG) sensor for biomedical application is described. The FBG sensor can be used to measure sound pressure and temperature rise simultaneously in biological tissues exposed to ultrasound. The theoretical maximum values that can be measured with the FBG sensor are 73.0 MPa and 30 °C.

Methods

In this study, measurement of sound pressure up to 5 MPa was performed at an ultrasound frequency of 2 MHz. A maximum temperature change of 6 °C was measured in a tissue-mimicking material.

Results

Values yielded by the FBG sensor agreed with those measured using a thermocouple and a hydrophone.

Conclusion

Since this sensor is used to monitor the sound pressure and temperature simultaneously, it can also be used for industrial applications, such as ultrasonic cleaning of semiconductors under controlled temperatures.

     

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.

     

PET Imaging of Human Brown Adipose Tissue with the TSPO Tracer [<Superscript>11</Superscript>C]PBR28

Purpose

Brown adipose tissue (BAT) in adult humans has been recently rediscovered and intensively investigated as a new potential therapeutic target for obesity and type 2 diabetes (T2D). However, reliable assessment of BAT mass in vivo represents a considerable challenge. The purpose of this investigation is to demonstrate for the first time that human BAT depots can be imaged with a translocator protein (TSPO)-specific positron emission tomography (PET) tracer [¹¹C]PBR28 under thermoneutral conditions.

Procedures

In this retrospective analysis, we analyzed the images of three healthy volunteers who underwent PET/magnetic resonance (MR) imaging after injection of 14 m Ci of [¹¹C]PBR28 at room temperature. Thirty-minute static PET images were reconstructed from the data obtained 60–90 min after the injection of the tracer.

Results

[¹¹C]PBR28 uptake in the neck/supraclavicular regions was identified, which was parallel to the known distribution pattern of human BAT depots. These areas co-localized with the areas of hyperintensity and corresponded to fat on T1-weighted MR images. Standardized uptake value (SUV) was used to quantify [¹¹C]PBR28 signal in BAT depots. The average (± SD) SUV_(mean) and SUV_max for BAT depots was 2.13 (± 0.33) and 3.19 (± 0.34), respectively, while the average SUV_(mean) for muscle and subcutaneous adipose tissue was 0.79 (± 0.1) and 0.18 (± 0.04), respectively.

Conclusions

In this brief article, we provide the first evidence suggesting that [¹¹C]PBR28, a widely available TSPO-specific PET tracer, can be used for imaging human BAT mass under thermoneutral conditions.

     

PET Imaging with <Emphasis Type="Italic">S</Emphasis>-[<Superscript>11</Superscript>C]Methyl-L-Cysteine and L-[<Emphasis Type="Italic">Methyl</Emphasis>-<Superscript>11</Superscript>C]Methionine in Rat Models of Glioma,Glioma Radiotherapy,and Neuroinflammation

Purpose

S-[¹¹C]-methyl-L-cysteine ([¹¹C]MCYS) has been claimed to offer higher tumor selectivity than L-[methyl- ¹¹C]methionine ([¹¹C]MET). We examined this claim in animal models.

Procedures

Rats with implanted untreated (n = 10) or irradiated (n = 7, 1 × 25 Gy, on day 8) orthotopic gliomas were scanned after 6, 9, and 12 days, using positron emission tomography. Rats with striatal injections of saline (n = 9) or bacterial lipopolysaccharide (n = 9) were scanned after 3 days.

Results

Uptake of the two tracers in untreated gliomas was similar. [¹¹C]MCYS was not accumulated in salivary glands, nasal epithelium, and healing wounds, in contrast to [¹¹C]MET, but showed 40 % higher accumulation in the healthy brain. Both tracers showed a reduced tumor uptake 4 days after irradiation and minor accumulation in inflamed striatum. [¹¹C]MCYS indicated higher lesion volumes than [¹¹C]MET (untreated tumor + 47 %; irradiated tumor up to + 500 %; LPS-inflamed striatum + 240 %).

Conclusions

[¹¹C]MCYS was less accumulated in some non-tumor tissues than [¹¹C]MET, but showed lower tumor-to-brain contrast.

     

Preliminary Results that Assess Metformin Treatment in a Preclinical Model of Pancreatic Cancer Using Simultaneous [<Superscript>18</Superscript>F]FDG PET and acidoCEST MRI

Purpose

We sought to determine if the synergy between evaluations of glucose uptake in tumors and extracellular tumor acidosis measured with simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) can improve longitudinal evaluations of the response to metformin treatment.

Procedures

A standard 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) PET protocol that evaluates glucose uptake in tumors, and a standard acidoCEST MRI protocol that measures extracellular pH (pHe) in tumors, were simultaneously performed to assess eight vehicle-treated (control) mice and eight metformin-treated mice 1 day before treatment, 1 day after initiating daily treatment with metformin, and 7 days after initiating treatment. Longitudinal changes in SUV_max and extracellular pH (pHe) were evaluated for each treatment group, and differences in SUV_max and pHe between metformin-treated and control groups were also evaluated.

Results

MRI acquisition protocols had little effect on the PET count rate, and the PET instrumentation had little effect on image contrast during acidoCEST MRI, verifying that [¹⁸F]FDG PET and acidoCEST MRI can be performed simultaneously. The average SUV_max of the tumor model had a significant decrease after 7 days of treatment with metformin, as expected. The average tumor pHe decreased after 7 days of metformin treatment, which reflected the inhibition of the consumption of cytosolic lactic acid caused by metformin. However, the average SUV_max of the tumor model was not significantly different between the metformin-treated and control groups after 7 days of treatment, and average pHe was also not significantly different between these groups. For comparison, the combination of average SUV_max and pHe measurements significantly differed between the treatment group and control group on Day 7.

Conclusions

[¹⁸F]FDG PET and acidoCEST MRI studies can be performed simultaneously. The synergistic combination of assessing glucose uptake and tumor acidosis can improve differentiation of a drug-treated group from a control group during drug treatment of a tumor model.