Biodistributions of 177Lu- and 111In-labeled 7E11 antibodies to prostate-specific membrane antigen in xenograft model of prostate cancer and potential use of 111In-7E11 as a pre-therapeutic agent for 177Lu-7E11 radioimmunotherapy.

INTRODUCTION: Prostate-specific membrane antigen is a transmembrane glycoprotein highly expressed in many prostate cancers and can be targeted with radiolabeled antibodies for diagnosis and treatment of this disease. To serve as a radioimmunotherapeutic agent, a kinetically inert conjugate is desired to maximize tumor uptake and tumor radiation dose with minimal nonspecific exposure to bone marrow and other major organs. MATERIALS AND METHODS: In this study, we assessed the pharmacokinetics and biodistribution of the 7E11 monoclonal antibody (MAb) radiolabeled with the lutetium-177 ((177)Lu)-tetraazacyclododecanetetraacetic acid conjugate system ((177)Lu-7E11) versus those of the 7E11 MAb radiolabeled with the indium-111 ((111)In)/glycyl-tyrosyl-(N,-diethylenetriaminepentaacetic acid)/lysine hydrochloride conjugate system ((111)In-7E11, also known as ProstaScint) to determine the feasibility of using (111)In-7E11 as a pre-therapeutic agent for (177)Lu-7E11 radioimmunotherapy. Pharmacokinetic and biodistribution studies of (177)Lu-7E11 in lymph node cancer of the prostate (LNCaP) xenograft mice were performed at 2, 8, 12, 24, 72, and 168 h after radiopharmaceutical administration. For (111)In-7E11, pharmacokinetic and biodistribution studies were performed at 8, 24, and 72 h. Parallel studies of (177)Lu-7E11 in non-tumor-bearing mice at 8, 24, and 72 h post-injection served as controls. Gamma scintigraphy was performed, followed by autoradiography and tissue counting, to demonstrate and quantify the distributions of radioconjugated MAb in the tumor and normal tissues. RESULTS AND DISCUSSION: Both (177)Lu- and (111)In-7E11 conjugates demonstrated an early blood pool phase in which uptake was dominated by the blood, lung, spleen and liver, followed by uptake and retention of the radiolabeled antibody in the tumor which was most prominent at 24 h. Total accumulation of radioconjugated MAb in tumor at 24 h was greater in the case of (177)Lu-7E11 in comparison to that of (111)In-7E11. Continued accumulation in tumor was observed for the entire time course studied for both (177)Lu-7E11 and (111)In-7E11. The liver was the only major organ demonstrating a significant difference in accumulation between the two conjugates. In conclusion, pharmacokinetic and biodistribution studies of (177)Lu-7E11 in LNCaP xenograft mouse models support its potential application as a radioimmunotherapeutic agent targeting prostate cancer, and the distribution and tumor uptake of (111)In-7E11 appear to be similar to those of (177)Lu-7E11, supporting its use as a pre-therapeutic tool to assess the potential accumulation of (177)Lu-7E11 radioimmunotherapeutic at sites of prostate cancer. However, the different accumulation patterns of the (111)In and (177)Lu immunoconjugates in liver will likely prevent the use of (111)In-7E11 as a true dosimetry tool for (177)Lu-7E11 radioimmunotherapy.

Small-animal SPECT and SPECT/CT: important tools for preclinical investigation.

The need to study dynamic biologic processes in intact small-animal models of disease has stimulated the development of high-resolution nuclear imaging methods. These methods are capable of clarifying molecular interactions important in the onset and progression of disease, assessing the biologic relevance of drug candidates and potential imaging agents, and monitoring therapeutic effectiveness of pharmaceuticals serially within a single-model system. Single-photon-emitting radionuclides have many advantages in these applications, and SPECT can provide 3-dimensional spatial distributions of gamma- (and x-) ray-emitting radionuclide imaging agents or therapeutics. Furthermore, combining SPECT with CT in a SPECT/CT system can assist in defining the anatomic context of biochemical processes and improve the quantitative accuracy of the SPECT data. Over the past decade, dedicated small-animal SPECT and SPECT/CT systems have been developed in academia and industry. Although significant progress in this arena has been realized through system development and biologic application, further innovation continues to address challenges in camera sensitivity, spatial resolution, and image reconstruction and quantification. The innumerable applications of small-animal SPECT and SPECT/CT in drug development, cardiology, neurology, and oncology are stimulating further investment in education, research, and development of these dedicated small-animal imaging modalities.

Quantitative accuracy of PET/CT for image-based kinetic analysis.

Accuracy in quantification of activity concentrations (e.g., in Bq/ml) is essential for compartment modeling and kinetic analysis of dynamic reconstructed PET images. Dynamic PET data can be acquired in list-mode, and often are preferred over frame mode acquisitions due to the flexibility of reformatting the list-mode data into different dynamic image sequences after the acquisition is complete. However, most PET data are acquired as static frames. It therefore is important to evaluate the quantitative accuracy of list-mode or dynamic PET acquisitions prior to their use for clinical or research applications. The quantitative accuracy of list-mode acquisitions obtained with a Siemens Biograph 16 PET/CT scanner at our institution was evaluated; the image data were acquired from an anthropomorphic phantom (Data Spectrum, Hillsborough, NC) filled with an aqueous solution of 18F-fluorodeoxyglucose (FDG). PET data were acquired with the phantom for the following three different configurations: (1) with nonradioactive water in the body compartment and aqueous solution of 18F-FDG in only a fillable cylindrical insert to simulate the first several seconds of highly concentrated radioactivity within the field of view such as that in major venous or pulmonary vessels or in the cardiac ventricles, (2) with radioactivity throughout the entire body compartment and imaged with 3 min static frames and 12 min in list-mode that was reformatted into four 3-min frames, and (3) with radioactivity throughout the body compartment and imaged in list-mode and reformatted into sequential time frames having durations of 3, 10, 20, 30, 50, and 67 s, respectively (i.e., total of 180 s). All measured concentration values were compared against values acquired from static images or against the actual activity concentrations calculated from the calibrated activities dispensed into the phantom corrected for physical decay of 18F. These analyses demonstrated that the count rate limitation is minimal or negligible as long as there is no more than 370-440 MBq (10-12 mCi) activity entirely within the axial FOV and that list-mode acquisition yields accurate quantitation of activity concentrations over a clinically realistic range of activities. In addition, reformatting a single list-mode acquisition into frames of different durations retains quantitative accuracy with respect to static frame data and compared to the known radionuclide concentration in the phantom. Within these constraints, the list-mode data acquired with the Biograph 16 PET/CT system are quantitatively accurate for image-based kinetic analysis.

Assessment of the sources of error affecting the quantitative accuracy of SPECT imaging in small animals.

Small animal SPECT imaging systems have multiple potential applications in biomedical research. Whereas SPECT data are commonly interpreted qualitatively in a clinical setting, the ability to accurately quantify measurements will increase the utility of the SPECT data for laboratory measurements involving small animals. In this work, we assess the effect of photon attenuation, scatter and partial volume errors on the quantitative accuracy of small animal SPECT measurements, first with Monte Carlo simulation and then confirmed with experimental measurements. The simulations modeled the imaging geometry of a commercially available small animal SPECT system. We simulated the imaging of a radioactive source within a cylinder of water, and reconstructed the projection data using iterative reconstruction algorithms. The size of the source and the size of the surrounding cylinder were varied to evaluate the effects of photon attenuation and scatter on quantitative accuracy. We found that photon attenuation can reduce the measured concentration of radioactivity in a volume of interest in the center of a rat-sized cylinder of water by up to 50% when imaging with iodine-125, and up to 25% when imaging with technetium-99m. When imaging with iodine-125, the scatter-to-primary ratio can reach up to approximately 30%, and can cause overestimation of the radioactivity concentration when reconstructing data with attenuation correction. We varied the size of the source to evaluate partial volume errors, which we found to be a strong function of the size of the volume of interest and the spatial resolution. These errors can result in large (>50%) changes in the measured amount of radioactivity. The simulation results were compared with and found to agree with experimental measurements. The inclusion of attenuation correction in the reconstruction algorithm improved quantitative accuracy. We also found that an improvement of the spatial resolution through the use of resolution recovery techniques (i.e. modeling the finite collimator spatial resolution in iterative reconstruction algorithms) can significantly reduce the partial volume errors.

Technological development and advances in single-photon emission computed tomography/computed tomography.

Single-photon emission computed tomography/computed tomography (SPECT/CT) has emerged during the past decade as a means of correlating anatomical information from CT with functional information from SPECT. The integration of SPECT and CT in a single imaging device facilitates anatomical localization of the radiopharmaceutical to differentiate physiological uptake from that associated with disease and patient-specific attenuation correction to improve the visual quality and quantitative accuracy of the SPECT image. The first clinically available SPECT/CT systems performed emission-transmission imaging using a dual-headed SPECT camera and a low-power x-ray CT subsystem. Newer SPECT/CT systems are available with high-power CT subsystems suitable for detailed anatomical diagnosis, including CT coronary angiography and coronary calcification that can be correlated with myocardial perfusion measurements. The high-performance CT capabilities also offer the potential to improve compensation of partial volume errors for more accurate quantitation of radionuclide measurement of myocardial blood flow and other physiological processes and for radiation dosimetry for radionuclide therapy. In addition, new SPECT technologies are being developed that significantly improve the detection efficiency and spatial resolution for radionuclide imaging of small organs including the heart, brain, and breast, and therefore may provide new capabilities for SPECT/CT imaging in these important clinical applications.

Correcting tumour SUV for enhanced bone marrow uptake: retrospective 18F-FDG PET/CT studies.

PURPOSE: The concentration of F-FDG in the bone marrow is usually low. One common cause of high uptake is due to bone marrow stimulating drugs administered in conjunction with chemotherapy or radiation therapy. It has been hypothesized that the sequestration of F-FDG to the bone marrow may reduce the standardized uptake value (SUV) of a tumour. We tested this hypothesis by quantifying total F-FDG uptake in the bone marrow of patients with visibly enhanced bone marrow uptake and computing its effect on tumour SUV. METHODS: Total F-FDG in bone marrow was measured in two groups of PET/CT studies: one (n=19) with visibly enhanced bone marrow, the other (n=5), a baseline group with 'normal' levels of uptake. To measure the F-FDG in bone marrow, the entire skeleton in the CT was segmented from surrounding tissue, and the resulting volume applied to the PET image. Using kinetic analysis we show that the predicted correction factor to tumour SUV is given by (1-q0/Q)/(1-q/Q), where Q is the injected dose, and q and q0 are enhanced and baseline bone marrow uptake (MBq). RESULTS: The enhanced bone marrow uptake averaged 8.9+/-3.2% of injected dose (15.2% max) vs. 4.2+/-0.4% (4.6% max) at baseline. This resulted in a predicted artificial decrease in tumour SUV of up to 11.5% (4.9+/-4.3%, on average). CONCLUSION: Enhanced bone marrow uptake is predicted to reduce tumour SUVs by as much as 11.5% in our patient group and is a potential confounding factor in using SUV for monitoring tumour response to therapy.

In vivo microCT imaging of rodent cerebral vasculature.

Computed tomography (CT) remains a critical diagnostic tool for evaluating patients with cerebrovascular disease, and the advent of specialized systems for imaging rodents has extended these techniques to small animal models of these diseases. We therefore have evaluated in vivo methods of imaging rat models of hemorrhagic stroke using a high resolution compact computed tomography ('microCT') system (FLEX(tm) X-O(tm), Gamma Medica-Ideas, Northridge, CA). For all in vivo studies, the head of the anesthetized rat was secured in a custom immobilization device for microCT imaging with 512 projections over 2 min at 60 kVp and 0.530 mA (I(tube) x t/rotation=63.6 mAs). First, imaging without iodinated contrast was performed (a) to differentiate the effect of contrast agent in contrast-enhanced CT and (b) to examine the effectiveness of the immobilization device between two time points of CT acquisitions. Then, contrast-enhanced CT was performed with continuous administration of iopromide (300 mgI ml(-1) at 1.2 ml min(-1)) to visualize aneurysms and other vascular formations in the carotid and cerebral arteries that may precede subarachnoid hemorrhage. The accuracy of registration between the noncontrast and contrast-enhanced CT images with the immobilization device was compared against the images aligned with normalized mutual information using FMRIB's linear image registration tool (FLIRT). Translations and rotations were examined between the FLIRT-aligned noncontrast CT image and the nonaligned noncontrast CT image. These two data sets demonstrated translational and rotational differences of less than 0.5 voxel (approximately 85 microm) and 0.5 degrees, respectively. Noncontrast CT demonstrated a very small volume (0.1 ml) of femoral arterial blood introduced surgically into the rodent brain. Continuous administration of iopromide during the CT acquisition produced consistent vascular contrast in the reconstructed CT images. As a result, carotid arteries and major cerebral blood vessels were visible with contrast-enhanced CT, but not with noncontrast CT. In conclusion, the CT-compatible immobilization device was useful for in vivo microCT imaging of intracranial blood and of vascular structures within and immediately adjacent to the rodent brain. The microCT imaging technique is also compatible with continuous administration of a conventional iodinated contrast agent (e.g. iopromide) and therefore does not require specialized small animal specific contrast agent that has comparatively long in vivo residence time.

Monte Carlo simulations of compact gamma cameras based on avalanche photodiodes.

Avalanche photodiodes (APDs), and in particular position-sensitive avalanche photodiodes (PSAPDs), are an attractive alternative to photomultiplier tubes (PMTs) for reading out scintillators for PET and SPECT. These solid-state devices offer high gain and quantum efficiency, and can potentially lead to more compact and robust imaging systems with improved spatial and energy resolution. In order to evaluate this performance improvement, we have conducted Monte Carlo simulations of gamma cameras based on avalanche photodiodes. Specifically, we investigated the relative merit of discrete and PSAPDs in a simple continuous crystal gamma camera. The simulated camera was composed of either a 4 x 4 array of four channels 8 x 8 mm2 PSAPDs or an 8 x 8 array of 4 x 4 mm2 discrete APDs. These configurations, requiring 64 channels readout each, were used to read the scintillation light from a 6 mm thick continuous CsI:Tl crystal covering the entire 3.6 x 3.6 cm2 photodiode array. The simulations, conducted with GEANT4, accounted for the optical properties of the materials, the noise characteristics of the photodiodes and the nonlinear charge division in PSAPDs. The performance of the simulated camera was evaluated in terms of spatial resolution, energy resolution and spatial uniformity at 99mTc (140 keV) and 125I ( approximately 30 keV) energies. Intrinsic spatial resolutions of 1.0 and 0.9 mm were obtained for the APD- and PSAPD-based cameras respectively for 99mTc, and corresponding values of 1.2 and 1.3 mm FWHM for 125I. The simulations yielded maximal energy resolutions of 7% and 23% for 99mTc and 125I, respectively. PSAPDs also provided better spatial uniformity than APDs in the simple system studied. These results suggest that APDs constitute an attractive technology especially suitable to build compact, small field of view gamma cameras dedicated, for example, to small animal or organ imaging.

Rodent brain imaging with SPECT/CT.

We evaluated methods of imaging rat models of stroke in vivo using a single photon emission computed tomography (SPECT) system dedicated to small animal imaging (X-SPECT, Gamma Medica-Ideas, Northridge, CA). An animal model of ischemic stroke was developed for in vivo SPECT/CT imaging using the middle cerebral artery occlusion (MCAO) technique. The presence of cerebral ischemia was verified in ex vivo studies using triphenyltetrazolium chloride (TTC) staining. In vivo radionuclide imaging of cerebral blood flow was performed in rats following MCAO using dynamic planar imaging of 99mTc-exametazime with parallel hole collimation. This was followed immediately by in vivo radionuclide imaging of cerebral blood flow with 99mTc-exametazime in the same animals using 1-mm pinhole SPECT. Correlated computed tomography imaging was performed to localize radiopharmaceutical uptake. The animals were allowed to recover and ex vivo autoradiography was performed with separate administration of 99mTc-exametazime. Time activity curve of 99mTc-exametazime showed that the radiopharmaceutical uptake could be maintained for over 9 min. The activity would be expected to be relatively stable for a much longer period, although the data were only obtained for 9 min. TTC staining revealed sizable infarcts by visual observation of inexistence of TTC stain in infracted tissues of MCAO rat brains. In vivo SPECT imaging showed cerebral blood flow deficit in the MCAO model, and the in vivo imaging result was confirmed with ex vivo autoradiography. We have demonstrated a capability of imaging regions of cerebral blood flow deficit in MCAO rat brains in vivo using a pinhole SPECT dedicated to small animal imaging.

Partial-volume correction in PET: validation of an iterative postreconstruction method with phantom and patient data.

UNLABELLED: Partial-volume errors (PVEs) in PET can cause incorrect estimation of radiopharmaceutical uptake in small tumors. An iterative postreconstruction method was evaluated that corrects for PVEs without a priori knowledge of tumor size or background. METHODS: Volumes of interest (VOIs) were drawn on uncorrected PET images. PVE-corrected images were produced using an iterative 3-dimensional deconvolution algorithm and a local point spread function. The VOIs were projected on the corrected image to estimate the PVE-corrected mean activity concentration. These corrected mean values were compared with uncorrected maximum and mean values. Simulated data were generated as a first test of the correction algorithm. Phantom measurements were made using (18)F-FDG-filled spheres in a scattering medium. Clinical validation used 154 surrogate tumors from 9 patients. The surrogate tumors were blood-pool images of the descending aorta as well as mesenteric and iliac arteries and veins. Surrogate tumors ranged in diameter from 5 to 25 mm. Analysis used (18)F-FDG and (11)C-CO datasets (both dynamic and static). Values representing "truth" were derived from imaging the blood pool in large structures (e.g., the left ventricle, left atrium, or sections of the aorta) where PVEs were negligible. Surrogate tumor sizes were measured from contrast CT. RESULTS: The PVE-correction technique, when applied to the mean value in spheric phantoms, yielded recovery coefficients of 87% for an 8-mm-diameter sphere and between 100% and 103% for spheres between 13 and 29 mm. For the human studies, PVE-corrected data recovered a large fraction of the true activity concentration (86% +/- 7% for an 8-mm-diameter tumor and 98% +/- 8% for tumors between 10 and 24 mm). For tumors smaller than 18 mm, the PVE-corrected mean values were less biased (P<0.05) than the uncorrected maximum or mean values. CONCLUSION: Iterative postreconstruction PVE correction generated more accurate uptake measurements in subcentimeter tumors for both phantoms and patients than the uncorrected values. The method eliminates the requirement for segmenting anatomic data and estimating tumor metabolic size or tumor background level. This technique applies a PVE correction to the mean voxel value within a VOI, yielding a more accurate estimate of uptake than the maximum voxel value.

The macrophage-stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans.

A better understanding of tumor metastasis requires development of animal models that authentically reproduce the metastatic process. By modifying an existing mouse model of breast cancer, we discovered that macrophage-stimulating protein promoted breast tumor growth and metastasis to several organs. A special feature of our findings was the occurrence of osteolytic bone metastases, which are prominent in human breast cancer. To explore the clinical relevance of our model, we examined expression levels of three genes involved in activation of the MSP signaling pathway (MSP, MT-SP1, and MST1R) in human breast tumors. We found that overexpression of MSP, MT-SP1, and MST1R was a strong independent indicator of both metastasis and death in human breast cancer patients and significantly increased the accuracy of an existing gene expression signature for poor prognosis. These data suggest that signaling initiated by MSP is an important contributor to metastasis of breast cancer and introduce an independent biomarker for assessing the prognosis of humans with breast cancer.

Progress in SPECT/CT imaging of prostate cancer.

Prostate cancer is the most common type of cancer (other than skin cancer) among men in the United States. Although prostate cancer is one of the few cancers that grow so slowly that it may never threaten the lives of some patients, it can be lethal once metastasized. Indium-111 capromab pendetide (ProstaScint, Cytogen Corporation, Princeton, NJ) imaging is indicated for staging and recurrence detection of the disease, and is particularly useful to determine whether or not the disease has spread to distant metastatic sites. However, the interpretation of 111In-capromab pendetide is challenging without correlated structural information mostly because the radiopharmaceutical demonstrates nonspecific uptake in the normal vasculature, bowel, bone marrow, and the prostate gland. We developed an improved method of imaging and localizing 111In-Capromab pendetide using a SPECT/CT imaging system. The specific goals included: i) development and application of a novel iterative SPECT reconstruction algorithm that utilizes a priori information from coregistered CT; and ii) assessment of clinical impact of adding SPECT/CT for prostate cancer imaging with capromab pendetide utilizing the standard and novel reconstruction techniques. Patient imaging studies with capromab pendetide were performed from 1999 to 2004 using two different SPECT/CT scanners, a prototype SPECT/CT system and a commercial SPECT/CT system (Discovery VH, GE Healthcare, Waukesha, WI). SPECT projection data from both systems were reconstructed using an experimental iterative algorithm that compensates for both photon attenuation and collimator blurring. In addition, the data obtained from the commercial system were reconstructed with attenuation correction using an OSEM reconstruction supplied by the camera manufacturer for routine clinical interpretation. For 12 sets of patient data, SPECT images reconstructed using the experimental algorithm were interpreted separately and compared with interpretation of images obtained using the standard reconstruction technique. The experimental reconstruction algorithm improved spatial resolution, reduced streak artifacts, and yielded a better correlation with anatomic details of CT in comparison to conventional reconstruction methods (e.g., filtered back-projection or OSEM with attenuation correction only). Images produced with the experimental algorithm produced a subjective improvement in the confidence of interpretation for 11 of 12 studies. There were also changes in interpretations for 4 of 12 studies although the changes were not sufficient to alter prognosis or the patient treatment plan.

A multipinhole small animal SPECT system with submillimeter spatial resolution.

Single photon emission computed tomography (SPECT) is an important technology for molecular imaging studies of small animals. In this arena, there is an increasing demand for high performance imaging systems that offer improved spatial resolution and detection efficiency. We have designed a multipinhole small animal imaging system based on position sensitive avalanche photodiode (PSAPD) detectors with the goal of submillimeter spatial resolution and high detection efficiency, which will allow us to minimize the radiation dose to the animal and to shorten the time needed for the imaging study. Our design will use 8 x 24 mm2 PSAPD detector modules coupled to thallium-doped cesium iodide [CsI(Tl)] scintillators, which can achieve an intrinsic spatial resolution of 0.5 mm at 140 keV. These detectors will be arranged in rings of 24 modules each; the animal is positioned in the center of the 9 stationary detector rings which capture projection data from the animal with a cylindrical tungsten multipinhole collimator. The animal is supported on a bed which can be rocked about the central axis to increase angular sampling of the object. In contrast to conventional SPECT pinhole systems, in our design each pinhole views only a portion of the object. However, the ensemble of projection data from all of the multipinhole detectors provide angular sampling that is sufficient to reconstruct tomographic data from the object. The performance of this multipinhole PSAPD imaging system was simulated using a ray tracing program that models the appropriate point spread functions and then was compared against the performance of a dual-headed pinhole SPECT system. The detection efficiency of both systems was simulated and projection data of a hot rod phantom were generated and reconstructed to assess spatial resolution. Appropriate Poisson noise was added to the data to simulate an acquisition time of 15 min and an activity of 18.5 MBq distributed in the phantom. Both sets of data were reconstructed with an ML-EM reconstruction algorithm. In addition, the imaging performance of both systems was evaluated with a uniformity phantom and a realistic digital mouse phantom. Simulations show that our proposed system produces a spatial resolution of 0.8 mm and an average detection efficiency of 630 cps/MBq. In contrast, simulations of the dual-headed pinhole SPECT system produce a spatial resolution of 1.1 mm and an average detection efficiency of 53 cps/MBq. These results suggest that our novel design will achieve high spatial resolution and will improve the detection efficiency by more than an order of magnitude compared to a dual-headed pinhole SPECT system. We expect that this system can perform SPECT with submillimeter spatial resolution, high throughput, and low radiation dose suitable for in vivo imaging of small animals.

A novel approach to multipinhole SPECT for myocardial perfusion imaging.

UNLABELLED: Myocardial perfusion imaging with SPECT remains critically important for diagnosing, assessing, and evaluating treatment of coronary artery disease. However, conventional rotational SPECT suffers from prolonged study times because of relatively low detection efficiency. We therefore have investigated a multipinhole collimator that could improve the detection efficiency in cardiac SPECT by a factor 5, while providing image quality comparable to standard rotational SPECT techniques using parallel-hole collimation. METHODS: We have measured the spatial resolution and efficiency of a 9-pinhole and a parallel-hole collimator mounted to a standard nuclear medicine gamma-camera as a function of distance from the collimator with a point source array. The efficiency was derived by integrating the detected counts, and the spatial resolution was determined from the full width at half maximum of the detected point spread function. In addition, we generated and reconstructed projection data of a 9-pinhole collimator from a digital heart phantom with a basal lesion. We simulated 3 scenarios: single view from left anterior, 2 views from left anterior and left lateral; and 4 views that include the 2 previous views and left lateral and anterior views. RESULTS: We found that the spatial resolution of the 9-pinhole collimator with 8-mm diameter pinholes was 30% poorer than that for the parallel-hole collimator, whereas the detection efficiency was increased by >10-fold. This predicts that a 9-pinhole collimator having the same spatial resolution as a parallel-hole collimator will have 5 times greater efficiency. Reconstructed data from 1 angular view of the 9-pinhole collimator showed the expected loss of spatial resolution in the longitudinal direction with reduced resolution of the basal lesion. In addition, the tomograms showed distortions in the apical region. In contrast, the reconstructed data from 2 and 4 views of the 9-pinhole collimator demonstrated good lesion definition and also produced images describing the shape and size of the heart more accurately. CONCLUSION: Our results indicate that myocardial multipinhole tomography with 2 or more views offers an image quality and spatial resolution comparable with current rotational SPECT techniques, but with the advantage of a 5-fold increase in efficiency.

Attenuation correction for small animal SPECT imaging using x-ray CT data.

Photon attenuation in small animal nuclear medicine scans can be significant when using isotopes that emit lower energy photons such as iodine-125. We have developed a method to use microCT data to perform attenuation corrected small animal single-photon emission computed tomography (SPECT). A microCT calibration phantom was first imaged, and the resulting calibration curve was used to convert microCT image values to linear attenuation coefficient values that were then used in an iterative SPECT reconstruction algorithm. This method was applied to reconstruct a SPECT image of a uniform phantom filled with 125I-NaI. Without attenuation correction, the image suffered a 30% decrease in intensity in the center of the image, which was removed with the addition of attenuation correction. This reduced the relative standard deviation in the region of interest from 10% to 6%.

Correction of photon attenuation and collimator response for a body-contouring SPECT/CT imaging system.

UNLABELLED: (111)In-Capromab pendetide imaging is indicated for postprostatectomy patients at risk for residual or recurrent disease. However, this study is complicated by relatively long times for tumor uptake and background washout that require imaging to be performed several days after radiopharmaceutical administration. In addition, (111)In-capromab pendetide demonstrates uptake in normal structures that produce images that are interpreted best using correlation with anatomic imaging. Finally, the visual quality of radionuclide imaging can be improved with corrections for photon attenuation and for the geometric response of the radionuclide collimator. Therefore, we have evaluated the advantages of using a commercially available dual-modality SPECT/CT system. In this article, we evaluate a novel iterative reconstruction algorithm using the SPECT/CT data obtained from phantoms and (111)In-capromab pendetide patient studies. METHODS: Phantom data acquired with the dual-head SPECT camera were reconstructed using both filtered backprojection (FBP) and an iterative maximum-likelihood expectation maximization (MLEM) algorithm incorporating corrections for (a) attenuation coefficient at the effective energy of the radionuclide (either (99m)Tc or (111)In) and (b) collimator response based on experimentally measured depth-dependent spatial resolution of the camera. The collimator response model used the coregistered CT image to estimate the source-target distances produced by the patient-contouring logic of the SPECT camera. Spatial resolution was measured using SPECT images of 2 line sources and uniformity from a uniform cylindric tank. Clinical (111)In-capromab pendetide SPECT/CT data were acquired according to the radiopharmaceutical manufacturer's protocol. Region-of-interest (ROI) analysis of a transverse slice at the level of the sacral base produced mean, median, maximum, and minimum counts per pixel for bone marrow and surrounding soft-tissue ROIs. Ratios of the mean capromab pendetide uptake within marrow to uptake within soft tissue were compared for images reconstructed with FBP versus that obtained from the MLEM method with photon attenuation and collimator response corrections. RESULTS: The source-target distances reconstructed from the patient-specific CT image agreed well with the corresponding values recorded manually from the camera display unit. This information was incorporated into the iterative reconstruction algorithms and improved the quality of SPECT images from phantoms and patients versus SPECT images reconstructed without the depth-dependent collimator response model. Qualitatively, SPECT images reconstructed with corrections for photon attenuation and collimator response showed less background activity and improved target contrast compared with those images reconstructed with FBP. The target-to-background ratio (marrow uptake-to-soft-tissue uptake) was significantly better using MLEM reconstruction than with FBP when mean uptake values were measured. CONCLUSION: A priori anatomic data can be used to enhance the quality of the SPECT image when reconstructed using iterative techniques (e.g., MLEM) that use the CT data to produce a patient-specific attenuation map and a collimator response model based on the body contour produced during the SPECT acquisition.

Calculation and validation of the use of effective attenuation coefficient for attenuation correction in In-111 SPECT.

Nuclear medicine tracers using 111In as a radiolabel are increasing in their use, especially in the domain of oncologic imaging. In these applications, it often is critical to have the capability of quantifying radionuclide uptake and being able to relate it to the biological properties of the tumor. However, images from single photon emission computed tomography (SPECT) can be degraded by photon attenuation, photon scattering, and collimator blurring; without compensation for these effects, image quality can be degraded, and accurate and precise quantification is impossible. Although attenuation correction for SPECT is becoming more common, most implementations can only model single energy radionuclides such as 99mTc and 123I. Thus, attenuation correction for 111In is challenging because it emits two photons (171 and 245 keV) at nearly equal rates (90.2% and 94% emission probabilities). In this paper, we present a method of calculating a single "effective" attenuation coefficient for the dual-energy emissions of 111In, and that can be used to correct for photon attenuation in radionuclide images acquired with this radionuclide. Using this methodology, we can derive an effective linear attenuation coefficient Micro(eff) and an effective photon energy E(eff) based on the emission probabilities and linear attenuation coefficients of the 111In photons. This approach allows us to treat the emissions from 111In as a single photon with an effective energy of 210 keV. We obtained emission projection data from a tank filled with a uniform solution of 111In. The projection data were reconstructed using an iterative maximum-likelihood algorithm with no attenuation correction, and with attenuation correction assuming photon energies of 171, 245, and 210 keV (the derived E(eff)). The reconstructed tomographic images demonstrate that the use of no attenuation correction, or correction assuming photon energies of 171 or 245 keV introduces inaccuracies into the reconstructed radioactivity distribution when compared against the effective energy method. In summary, this work provides both a theoretical framework and experimental methodology of attenuation correction for the dual-energy emissions from 111In. Although these results are specific to 111In, the foundation could easily be extended to other multiple-energy isotopes.

Radiation dose estimate in small animal SPECT and PET.

Calculations of radiation dose are important in assessing the medical and biological implications of ionizing radiation in medical imaging techniques such as SPECT and PET. In contrast, radiation dose estimates of SPECT and PET imaging of small animals are not very well established. For that reason we have estimated the whole-body radiation dose to mice and rats for isotopes such as 18F, 99mTc, 201Tl, (111)In, 123I, and 125I that are used commonly for small animal imaging. We have approximated mouse and rat bodies with uniform soft tissue equivalent ellipsoids. The mouse and rat sized ellipsoids had a mass of 30 g and 300 g, respectively, and a ratio of the principal axes of 1:1:4 and 0.7:1:4. The absorbed fractions for various photon energies have been calculated using the Monte Carlo software package MCNP. Using these values, we then calculated MIRD S-values for two geometries that model the distribution of activity in the animal body: (a) a central point source and (b) a homogeneously distributed source, and compared these values against S-value calculations for small ellipsoids tabulated in MIRD Pamphlet 8 to validate our results. Finally we calculated the radiation dose taking into account the biological half-life of the radiopharmaceuticals and the amount of activity administered. Our calculations produced S-values between 1.06 x 10(-13) Gy/Bq s and 2.77 x 10(-13) Gy/Bq s for SPECT agents, and 15.0 x 10(-13) Gy/Bq s for the PET agent 18F, assuming mouse sized ellipsoids with uniform source distribution. The S-values for a central point source in an ellipsoid are about 10% higher than the values obtained for the uniform source distribution. Furthermore, the S-values for mouse sized ellipsoids are approximately 10 times higher than for the rat sized ellipsoids reflecting the difference in mass. We reviewed published data to obtain administered radioactivity and residence times for small animal imaging. From these values and our computed S-values we estimated that the whole body dose in small animals ranges between 6 cGy and 90 cGy for mice and between about 1 cGy and 27 cGy for rats. The whole body dose in small animal imaging can be very high in comparison to the lethal dose to mice (LD50/30 approximately 7 Gy). For this reason the dose in small animal imaging should be monitored carefully and the administered activity should be kept to a minimum. These results also underscore the need of further development of instrumentation that improves detection efficiency and reduces radiation dose in small animal imaging.

X-ray-based attenuation correction for positron emission tomography/computed tomography scanners.

A synergy of positron emission tomography (PET)/computed tomography (CT) scanners is the use of the CT data for x-ray-based attenuation correction of the PET emission data. Current methods of measuring transmission use positron sources, gamma-ray sources, or x-ray sources. Each of the types of transmission scans involves different trade-offs of noise versus bias, with positron transmission scans having the highest noise but lowest bias, whereas x-ray scans have negligible noise but the potential for increased quantitative errors. The use of x-ray-based attenuation correction, however, has other advantages, including a lack of bias introduced from post-injection transmission scanning, which is an important practical consideration for clinical scanners, as well as reduced scan times. The sensitivity of x-ray-based attenuation correction to artifacts and quantitative errors depends on the method of translating the CT image from the effective x-ray energy of approximately 70 keV to attenuation coefficients at the PET energy of 511 keV. These translation methods are usually based on segmentation and/or scaling techniques. Errors in the PET emission image arise from positional mismatches caused by patient motion or respiration differences between the PET and CT scans; incorrect calculation of attenuation coefficients for CT contrast agents or metallic implants; or keeping the patient's arms in the field of view, which leads to truncation and/or beam-hardening (or x-ray scatter) artifacts. Proper interpretation of PET emission images corrected for attenuation by using the CT image relies on an understanding of the potential artifacts. In cases where an artifact or bias is suspected, careful inspection of all three available images (CT and PET emission with and without attenuation correction) is recommended.

Pinhole single-photon emission computed tomography for myocardial perfusion imaging of mice.

OBJECTIVES: Although transgenic mice have emerged as powerful experimental models of cardiovascular disease, methods for in vivo phenotypic assessment and characterization remain limited, motivating the development of new instruments for biologic measurement. BACKGROUND: We have developed a single-photon emission computed tomography system with a pinhole collimator (pinhole SPECT) for high-resolution cardiovascular imaging of mice. In this study, we describe a protocol for myocardial perfusion imaging of mice using technetium-99m ((99m)Tc)-sestamibi and demonstrate the feasibility for measurement of perfusion defect size from pinhole SPECT images. METHODS: Mice were anesthetized and injected with 370 MBq (10 mCi) of (99m)Tc-sestamibi. Tomographic projection images were acquired by rotating each mouse in a vertical axis in front of a stationary clinical scintillation camera equipped with a pinhole collimator. BALB/c mice (n = 15) were imaged after the permanent ligation of the left anterior descending coronary artery. The resulting defect size was measured from circumferential profiles of short-axis images. After imaging, the hearts were excised and sectioned to obtain ultra-high resolution digital autoradiographs of (99m)Tc-sestamibi, from which the actual infarct size was determined. RESULTS: Reconstructed image quality was equivalent to that obtained for clinical myocardial perfusion imaging. Linear regression analysis produced a correlation coefficient of 0.83 (p < 0.001) between the measured and actual values of the defect size. CONCLUSIONS: These results demonstrate that myocardial perfusion can be characterized qualitatively and quantitatively in mice using pinhole SPECT.