Maarten Brom

Spatial Resolution and Sensitivity of the Inveon Small-Animal PET Scanner

The Inveon small-animal PET scanner is characterized by a large, 127-mm axial length and a 161-mm crystal ring diameter. The associated high sensitivity is obtained by using all lines of response (LORs) up to the maximum ring difference (MRD) of 79, for which the most oblique LORs form acceptance angles of 38.3° with transaxial planes. The result is 2 phenomena that are normally not encountered in PET scanners: a parallax or depth-of-interaction effect in the axial direction and the breakdown of Fourier rebinning (FORE). Both effects cause a deterioration of axial spatial resolution. Limiting the MRD to smaller values reduces this axial blurring at the cost of sensitivity. Alternatively, 3-dimensional (3D) reconstruction techniques can be used in which the rebinning step is absent. The aim of this study was to experimentally determine the spatial resolution and sensitivity of the Inveon for its whole field of view (FOV). Methods: Spatial resolution and sensitivity were measured using filtered backprojection (FBP) with FORE, FBP with LOR angle-weighted adapted FORE (AFORE), and 3D ordered-subset expectation maximization followed by maximum a posteriori reconstruction (OSEM3D/MAP). Results: Tangential and radial full width at half maximum (FWHM) showed almost no dependence on the MRD using FORE and FBP. Tangential FWHMs were 1.5 mm in the center of the FOV (CFOV) and 1.8 mm at the edge of the FOV (EFOV). Radial FWHMs were 1.5 and 3.0 mm in the CFOV and EFOV, respectively. In contrast, axial FWHMs increased with the MRD and ranged between 1.1 and 2.0 mm in the CFOV and between 1.5 and 2.7 mm in the EFOV for a MRD between 1 and 79. AFORE improved the axial resolution for a large part of the FOV, but image noise increased. OSEM3D/MAP yielded uniform spatial resolution in all directions, with an average FWHM of 1.65 ± 0.06 mm. Sensitivity in the CFOV for the default energy and coincidence time window was 0.068; peak sensitivity was 0.111. Conclusion: The Inveon showed high spatial resolution and high sensitivity, both of which can be maintained using OSEM3D/MAP reconstruction instead of rebinning and 2D algorithms.

Image-quality assessment for several positron emitters using the NEMA NU 4-2008 standards in the Siemens Inveon small-animal PET scanner.

The positron emitters 18F, 68Ga, 124I, and 89Zr are all relevant in small-animal PET. Each of these radionuclides has different positron energies and ranges and a different fraction of single photons emitted. Average positron ranges larger than the intrinsic spatial resolution of the scanner (for 124I and 68Ga) will deteriorate the effective spatial resolution and activity recovery coefficient (RC) for small lesions or phantom structures. The presence of single photons (for 124I and 89Zr) could increase image noise and spillover ratios (SORs). Methods: Image noise, expressed as percentage SD in a uniform region (%SD), RC, and SOR (in air and water) were determined using the NEMA NU 4 small-animal image-quality phantom filled with 3.7 MBq of total activity of 18F, 68Ga, 124I, or 89Zr. Filtered backprojection (FBP), ordered-subset expectation maximization in 2 dimensions, and maximum a posteriori (MAP) reconstructions were compared. In addition to the NEMA NU 4 image-quality parameters, spatial resolutions were determined using small glass capillaries filled with these radionuclides in a water environment. Results: The %SD for 18F, 68Ga, 124I, and 89Zr using FBP was 6.27, 6.40, 6.74, and 5.83, respectively. The respective RCs were 0.21, 0.11, 0.12, and 0.19 for the 1-mm-diameter rod and 0.97, 0.65, 0.64, and 0.88 for the 5-mm-diameter rod. SORs in air were 0.01, 0.03, 0.04, and 0.01, respectively, and in water 0.02, 0.10, 0.13, and 0.02. Other reconstruction algorithms gave similar differences between the radionuclides. MAP produced the highest RCs. For the glass capillaries using FBP, the full widths at half maximum for 18F, 68Ga, 124I, and 89Zr were 1.81, 2.46, 2.38, and 1.99 mm, respectively. The corresponding full widths at tenth maximum were 3.57, 6.52, 5.87, and 4.01 mm. Conclusion: With the intrinsic spatial resolution (≈1.5 mm) of this latest-generation small-animal PET scanner, the finite positron range has become the limiting factor for the overall spatial resolution and activity recovery in small structures imaged with 124I and 68Ga. The presence of single photons had only a limited effect on the image noise. MAP, as compared with the other reconstruction algorithms, increased RC and decreased %SD and SOR.

Obstacles on the way to the clinical visualisation of beta cells: looking for the Aeneas of molecular imaging to navigate between Scylla and Charybdis.

For more than a decade, researchers have been trying to develop non-invasive imaging techniques for the in vivo measurement of viable pancreatic beta cells. However, in spite of intense research efforts, only one tracer for positron emission tomography (PET) imaging is currently under clinical evaluation. To many diabetologists it may remain unclear why the imaging world struggles to develop an effective method for non-invasive beta cell imaging (BCI), which could be useful for both research and clinical purposes. Here, we provide a concise overview of the obstacles and challenges encountered on the way to such BCI, in both native and transplanted islets. We discuss the major difficulties posed by the anatomical and cell biological features of pancreatic islets, as well as the chemical and physical limits of the main imaging modalities, with special focus on PET, SPECT and MRI. We conclude by indicating new avenues for future research in the field, based on several remarkable recent results.

Development of Radiotracers for the Determination of the Beta-Cell Mass In Vivo

The changes in beta-cell mass (BCM) during the course of diabetes are not yet well characterized. A non-invasive method to measure the BCM in vivo would allow us to study the BCM during the onset and progression of the diseases caused by beta-cell dysfunction. PET and SPECT imaging are attractive approaches to determine the BCM because of their high sensitivity and the possibility to quantitatively analyze the images. Several targets and their corresponding radiotracers have been examined for their ability to determine the BCM including radiolabeled antibodies, antibody fragments, peptides and small molecules. Although some of these tracers show promising results, there is still no reliable method to determine the beta-cell mass in vivo. In this review, the targets and the corresponding radiotracers evaluated so far for the determination of the BCM in vivo in humans will be discussed.

Radiolabelled GLP-1 analogues for in vivo targeting of insulinomas.

Internalizing agonists are usually selected for peptide receptor targeting. There is increasing evidence that non-internalizing receptor antagonists can be used for this purpose. We investigated whether the glucagon-like peptide-1 receptor (GLP-1R) antagonist exendin(9-39) can be used for in vivo targeting of GLP-1R expressing tumours and compared the in vitro and in vivo characteristics with the GLP-1R agonists exendin-3 and exendin-4. The binding and internalization kinetics of labelled [Lys(40) (DTPA)]exendin-3, [Lys(40) (DTPA)]exendin-4 and [Lys(40) (DTPA)]exendin(9-39) were determined in vitro using INS-1 cells. The in vivo targeting properties of [Lys(40) ((111) In-DTPA)]exendin-3, [Lys(40) ((111) In-DTPA)]exendin-4 and [Lys(40) ((111) In-DTPA)]exendin(9-39) were examined in BALB/c nude mice with subcutaneous INS-1 tumours. (nat) In-labelled [Lys(40) (DTPA)]exendin-3, [Lys(40) (DTPA)]exendin-4 and [Lys(40) (DTPA)]exendin(9-39) exhibited similar IC(50) values (13.5, 14.4 and 13.4 n m, respectively) and bound to 26 × 10(3) , 41 × 10(3) and 37 × 10(3) receptors per cell, respectively. [Lys(40) ((111) In-DTPA)]exendin-3 and [Lys(40) ((111) In-DTPA)]exendin-4 showed rapid in vitro binding and internalization kinetics, whereas [Lys(40) ((111) In-DTPA)]exendin(9-39) showed lower binding and minimal internalization in vitro. In mice, high specific uptake of [Lys(40) ((111) In-DTPA)]exendin-3 [25.0 ± 6.0% injected dose (ID) g(-1) ] in the tumour was observed at 0.5 h post-injection (p.i.) with similar uptake up to 4 h p.i. [Lys(40) ((111) In-DTPA)]exendin-4 showed higher tumour uptake at 1 and 4 h p.i. (40.8 ± 7.0 and 41.9 ± 7.2% ID g(-1), respectively). Remarkably, [Lys(40) ((111) In-DTPA)]exendin(9-39) showed only low specific uptake in the tumour at 0.5 h p.i. (3.2 ± 0.7% ID g(-1)), rapidly decreasing over time. In conclusion, the GLP-1R agonists [Lys(40) (DTPA)]exendin-3 and [Lys(40) (DTPA)]exendin-4 labelled with (111) In could be useful for in vivo GLP-1R targeting, whereas [Lys(40) (DTPA)]exendin(9-39) is not suited for in vivo targeting of the GLP-1R.

Improved labelling of DTPA- and DOTA-conjugated peptides and antibodies with 111In in HEPES and MES buffer

BackgroundIn single photon emission computed tomography [SPECT], high specific activity of 111In-labelled tracers will allow administration of low amounts of tracer to prevent receptor saturation and/or side effects. To increase the specific activity, we studied the effect of the buffer used during the labelling procedure: NaAc, NH4Ac, HEPES and MES buffer. The effect of the ageing of the 111InCl3 stock and cadmium contamination, the decay product of 111In, was also examined in these buffers.MethodsEscalating amounts of 111InCl3 were added to 1 μg of the diethylene triamine pentaacetic acid [DTPA]- and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA]-conjugated compounds (exendin-3, octreotide and anti-carbonic anhydrase IX [CAIX] antibody). Five volumes of 2-(N-morpholino)ethanesulfonic acid [MES], 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid [HEPES], NH4Ac or NaAc (0.1 M, pH 5.5) were added. After 20 min at 20°C (DTPA-conjugated compounds), at 95°C (DOTA-exendin-3 and DOTA-octreotide) or at 45°C (DOTA-anti-CAIX antibody), the labelling efficiency was determined by instant thin layer chromatography. The effect of the ageing of the 111InCl3 stock on the labelling efficiency of DTPA-exendin-3 as well as the effect of increasing concentrations of Cd2+ (the decay product of 111In) were also examined.ResultsSpecific activities obtained for DTPA-octreotide and DOTA-anti-CAIX antibody were five times higher in MES and HEPES buffer. Radiolabelling of DTPA-exendin-3, DOTA-exendin-3 and DTPA-anti-CAIX antibody in MES and HEPES buffer resulted in twofold higher specific activities than that in NaAc and NH4Ac. Labelling of DTPA-exendin-3 decreased with 66% and 73% for NaAc and NH4Ac, respectively, at day 11 after the production date of 111InCl3, while for MES and HEPES, the maximal decrease in the specific activity was 10% and 4% at day 11, respectively. The presence of 1 pM Cd2+ in the labelling mixture of DTPA-exendin-3 in NaAc and NH4Ac markedly reduced the labelling efficiency, whereas Cd2+ concentrations up to 0.1 nM did not affect the labelling efficiency in MES and HEPES buffer.ConclusionsWe showed improved labelling of DTPA- and DOTA-conjugated compounds with 111In in HEPES and MES buffer. The enhanced labelling efficiency appears to be due to the reduced competitive chelation of cadmium. The enhanced labelling efficiency will allow more sensitive imaging of the biomarkers with SPECT.

Beta cell imaging - a key tool in optimized diabetes prevention and treatment

The prevalence of diabetes is 382 million worldwide, and is expected to rise to 592 million in 2035 (http://www.idf.org/diabetesatlas); 2.5-15% of national annual healthcare budgets are related to diabetes care, potentially increasing to 40% in high-prevalence countries. Beta cell dysfunction and death are central events in diabetes pathogenesis, but the natural history of beta cell loss remains unknown. Clinical imaging of beta cells will play a pivotal role in developing strategies for optimized diabetes prevention and treatment.

In vivo imaging of beta cells with radiotracers: state of the art, prospects and recommendations for development and use

Radiotracer imaging is characterised by high in vivo sensitivity, with a detection limit in the lower picomolar range. Therefore, radiotracers represent a valuable tool for imaging pancreatic beta cells. High demands are made of radiotracers for in vivo imaging of beta cells. Beta cells represent only a small fraction of the volume of the pancreas (usually 1–3%) and are scattered in the tiny islets of Langerhans throughout the organ. In order to be able to measure a beta cell-specific signal, one has to rely on highly specific tracer molecules because current in vivo imaging technologies do not allow the resolution of single islets in humans non-invasively. Currently, a considerable amount of preclinical data are available for several radiotracers and three are under clinical evaluation. We summarise the current status of the evaluation of these tracer molecules and put forward recommendations for their further evaluation.

111In-exendin uptake in the pancreas correlates with the beta cell mass and not with the alpha cell mass

Targeting of the GLP-1 receptor with 111In-labeled exendin is an attractive approach to determine the β-cell mass (BCM). Preclinical studies as well as a proof-of-concept study in type 1 diabetic patients and healthy subjects showed a direct correlation between BCM and radiotracer uptake. Despite these promising initial results, the influence of α-cells on the uptake of the radiotracer remains a matter of debate. In this study, we determined the correlation between pancreatic tracer uptake and β- and α-cell mass in a rat model for β-cell loss. The uptake of 111In-exendin (% ID/g) showed a strong positive linear correlation with the BCM (Pearson r = 0.82). The fraction of glucagon-positive cells in the total endocrine mass was increased after alloxan treatment (26% ± 4%, 43% ± 8%, and 69% ± 21% for 0, 45, and 60 mg/kg alloxan, respectively). The uptake of 111In-exendin showed a negative linear correlation with the α-cell fraction (Pearson r = −0.76). These data clearly indicate toward specificity of 111In-exendin for β-cells and that the influence of the α-cells on 111In-exendin uptake is negligible.

Preclinical evaluation of 68Ga-DOTA-minigastrin for the detection of cholecystokinin-2/gastrin receptor-positive tumors

In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0) showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET), which could improve image quality. Targeting of cholecystokinin-2 (CCK2)/gastrin receptor-positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET-computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g), indicating CCK2/gastrin receptor-mediated uptake (p = .0005). The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor-positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor-positive tumors in humans.