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SPECT/PET > Background Section

SPECT/PET KIdney Imaging

Nuclear techniques are essential for the quantitative assessment of kidney function and for imaging molecular activity in small animals. We recently completed a major renovation and expansion of our PET/SPECT radiochemistry facilities, which have enabled a larger number of tracers to be studied. FDG, FLT, 64Cu-ATSM, and 18F-MISO are routinely available for PET studies and could potentially be utilized in the assessment of renal function, cellular proliferation and hypoxia. Our newly acquired NanoSPECT system provides helical scanning for uniform sensitivity and axial resolution, dynamic imaging capability, multiple energy windows for simultaneous dual-isotope acquisition, and interchangeable apertures (with between seven to ten pinholes each) for flexibility in selecting spatial resolution and sensitivity to best suit individual studies. This combination of sensitivity and angular sampling enables dynamic SPECT images to be obtained on the minute timescale and is suitable for the characterization of tracer kinetics through the kidneys. There are a wide number of radionuclides suitable for SPECT studies that are readily available (99mTc, 123I, 125I, 111In, 201Tl). Having these options for radiolabeling molecules of interest for imaging gives flexibility in the labeling chemistry, and the corresponding range of radioactive half-lives allows an investigator to pick one commensurate with the kinetics of the molecule to be labeled. In addition, there are many standard radiotracers for SPECT that are available either as kits or that can be synthesized in a relatively straightforward manner.

Assessment of Kidney Hypoxia using 64CuATSM and 18FMISO PET imaging: Recent studies have emphasized the role of hypoxia in the tubulointerstitium as a final common pathway to end-stage renal failure (1). When advanced, tubulointerstitial damage is associated with the loss of peritubular capillaries. Associated interstitial fibrosis impairs oxygen diffusion and supply to tubular and interstitial cells. Hypoxia of tubular cells leads to apoptosis or epithelial-mesenchymal transdifferentiation. This in turn exacerbates fibrosis of the kidney and subsequent chronic hypoxia, setting in train a vicious cycle whoseend point is ESRD. A number of mechanisms that induce tubulointerstitial hypoxia have been identified, including glomerular injury and vasoconstriction of efferent arterioles as a result of imbalances in vasoactive substances to decrease postglomerular peritubular capillary blood flow. Therapeutic approaches that target the tubulointerstitial hypoxia is thought to be effective against a broad range of renal diseases.
The current “gold standard” approaches for detecting tissue hypoxia are the polarographic oxygen-sensor and the exogenous histological agent pimonidazole (2, 3, 4). However, both these methods are invasive and are prone to sampling errors, which has led to the development of non-invasive imaging markers of hypoxia. Two commonly utilized PET radiotracers for imaging tumor hypoxia are 18F-fluoromisinidazole, 18FMISO, and 64Cu diacetyl-bis(N4-methylthiosemicarbazone), 64CuATSM (5, 6). These compounds diffuse into normally oxygenated and hypoxic cells but are chemically reduced and retained in substantially higher concentrations in the latter tissues, which can be detected by PET imaging. The FMISO tracer is more heavily utilized than CuATSM primarily because of its structural similarity with pimonidazole. However, an advantage of 64CuATSM is its long half-life (12.7 hrs) enabling images to be acquired many hours after tracer administration when non-specific retention and background levels should be minimized. Many studies have demonstrated the potential of these tracers to identify hypoxic tumor tissue and predict treatment response in both clinical and experimental settings (7, 8, 9, 10). The application of hypoxia sensitive radiotracers to pathologies other than cancer, especially those of the kidney, is a relatively unexplored area of research but could potentially play an important role in characterizing renal hypoxia and determining its role in disease development and prognosis.

(Preliminary CuATSM Imaging Results)
To assess the potential of 64CuATSM kidney imaging we acquired PET images of a control mouse 1 hour and 24 hours after tracer injection. Two time points were assessed because recent studies have demonstrated that in some cancer types, 64CuATSM uptake at time points early after administration is dominated by blood flow rather than hypoxia. This blood flow dependent uptake and retention was not seen 24 hours after injection. In our studies 64CuATSM was typically found to be isolated in the kidney cortex at both time points but at relatively low levels compared to that found in the liver, which is the primary excretion route. Figure S1 illustrates an axial image taken from this dataset. The kidneys are outlined in green. These images demonstrate that the background levels of 64CuATSM uptake inside the kidneys is relatively low. Thus, any specific uptake of the tracer due to the presence of hypoxia should readily be detected especially in the medulla.

(Developmental Hypoxia Imaging Studies)
Although PET imaging of tumor hypoxia has been shown to be effective for the detection of tissue with pO2 values less than 10 mmHg, its use for detecting renal hypoxia in mice has yet to be evaluated. The following studies will be performed to validate the use of this technique. Ischemia/reperfusion and HgCl2 will be used to generate an acute kidney injury model in mice. One day after injury mice will be injected with 64Cu-ATSM (or 18FMISO) and pimonidazole and then imaged using the microPET system. Following the PET scan mice will be sacrificed, the kidneys will be excised and snap frozen for histological and autoradiographic analysis. The spatial correlation between pimonidazole and radiotracer uptake will be quantified. Similar methods have been used by our lab to validate the sensitivity of radiotracers to hypoxia found in tumor tissue. For comparison we will also acquire Oxylite measures of absolute pO2 values within both kidneys using methods described above. This will be used to help determine the pO2 threshold for radiotracer uptake.

(Additional Developments in PET imaging)
Renovation of the PET radiochemistry laboratory, completed in 2006, included installation of state-of-the-art chemistry modules for remote synthesis of 18F and 11C labeled radiotracers starting with Curie quantities of cyclotron-generated radionuclide, facilities for manipulation of lower levels of other positron-emitting radionuclides such as 64Cu and 124I, as well as single-photon radionuclides, like 111In, 99mTc, and 123I. Radiotracers pertinent to kidney imaging that are currently available include [18F]FDG (fluorodeoxyglucose), [18F]FLT (fluorodeoxythymidine), [18F]fallypride, [11C]acetate, [64Cu]Cu-ATSM, as well as [99mTc]Tc-Annexin-V for SPECT. The Imaging Core will develop the protocols for successful studies of small animals as these isotopes are introduced, and will be responsible for appropriately modeling their kinetics for extracting quantitative data. Quantitative PET kinetic modeling of kidneys usually requires knowledge of the arterial input function (AIF), and we are developing a method to obtain the AIF directly from the image data through the use of an ensemble learning, independent-component analysis technique. Many VKDC investigators hope to utilize PET imaging in their individual research projects and, therefore, all potentially stand to benefit from these quantitative modeling techniques.

Assessment of Blood flow and Tubular Function with MAG3 SPECT imaging: Technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) is a renal radiopharmaceutical that was first introduced in 1986 (11, 12). Because of its favorable imaging characteristics, and efficient renal extraction, 99mTc-MAG3 has become the renal radiopharmaceutical of choice in many clinical centers to estimate split renal function and kidney transplant function, and to detect renal drainage abnormalities (13). Furthermore, the use of 3D 99mTc-MAG3 SPECT imaging also allows us to visualize regional changes, which could potentially be a useful tool for the detection of functional and anatomical regional abnormalities within the kidney. Recently this technique was reported to detect renal damage in the kidney ischemia/reperfusion mouse models (14). Since MAG3 SPECT is minimally invasive, cost effective and sensitive, it could also serve as an important tool for VKDC investigators allowing renal function to be assessed in the same animals at frequent intervals during the course of kidney disease.
The clearance of MAG3 is similar to PAH, and closely correlated to renal blood flow. MAG3 is actively excreted by proximal tubular cells at a very high rate of 50% - 60% per pass. Only 2%-5% of blood MAG3 is filtered through glomeruli per pass because of protein binding (15, 16). After an intravenous bolus injection, MAG3 quickly accumulates in the kidney. The speed and the amount of the MAG3 extraction in the kidney are strongly correlated with renal blood perfusion and the ability of proximal tubules to secrete MAG3 (17). The MAG3 that is extracted in the kidney then travels through the cortex into the medulla, and finally into the ureter and bladder. In a dynamic MAG3 renogram, the initial, rapidly rising ascending segment is due to early tubular extraction that depends on renal blood flow and tubule function. The rapidly descending phase of the MAG3 curve provides an assessment of the drainage function of the kidney-ureteral system (18, 19). Several quantitative methods have been developed to describe dynamic MAG3 renogram images: cortical transit time and the time to peak activity are useful indices of renal perfusion; the ratio of renal radioactivity 20 min to 3 min after injection and the percentage of peak activity retained at 20 min are indices of renal excretory function (14, 18, 19). Due to the high extraction efficiency and the dramatic double exponential initial decline in the plasma activity, MAG3 SPECT provides superior image quality. Furthermore, using ROI image analysis, MAG3 accumulation in a certain part of the kidney can be visualized and quantified over time (20), which can provide additional information about the function of a certain region within the kidney.

(Preliminary MAG3 Imaging Results)
To evaluate the utility of MAG3 for the assessment of mouse kidney function we collected planar dynamic images in a control mouse and 3D dynamic SPECT images in a mouse whose right kidney had been clamped for 30 minutes. The planar images are shown in Figure S2. As is typical in patient studies MAG3 was only observed in the kidneys and bladder of the mouse. Figure S3 shows the dynamic time courses of the MAG3 uptake and clearance derived from the planar images within the kidneys and bladder. These time courses can be used to derive estimates of renal blood blow and the tubular excretion rate. This approach was recently used in a mouse ischemia reperfusion model and found slower tubular excretion in kidneys that had been clamped as compared to sham kidneys (14). We also sought to advance this approach by performing full 3D SPECT dynamic imaging of MAG3 clearance in a similar ischemia reperfusion mouse model. This approach allows regional differences to be quantified (such as differences in the cortex and medulla). Figure S4 is an example MAG3 image taken from such a dataset. Examination of the derived time courses from this data revealed impaired MAG3 clearance in the impaired kidney.



(Developmental MAG3 Studies)
Although MAG3 SPECT imaging has been shown to offer unique advantage to measure renal function in human and rat, its use in mice has not been fully developed. During our pilot experiments, we have optimized the dose of the MAG3 and data acquisition during SPECT imaging process in mice. The following studies will be performed to further validate the use of this technique in mice to assess kidney function, particularly renal blood flow.
1. To validate the use of MAG3 SPECT to assess renal blood flow (RBF) in mice. A partial occlusion model will be used to modulate renal blood flow. Briefly, the left kidney will be removed and the blood flow to the right kidney will be manipulated by partially occluding the right renal artery. Renal blood flow will be determined by PAH clearance under isoflurane-anesthetized conditions (see pathophysiology and physiology core for detailed method). Glomerular filtration rate (GFR) will also be determined using FITC-inulin clearance. Within a week, the same mouse will undergo MAG3 SPECT imaging. Peak%ID (percentage of kidney peak activity in injected dose), time to peak, Peak:10 min ratio, %ID(10 – 40 s) will be calculated. MAG3 clearance will also be calculated according to method described by Bocher et al (20). The correlation of these indices with renal blood flow as determined by PAH clearance will be analyzed. Through this experiment, we hope that we can identify one or more of the MAG3 SPECT indices that best reflect the change in renal blood flow.
2. To examine the correlation between MAG3 SPECT derived kinetic parameters and renal function in a mouse model of acute kidney injury (AKI). Ischemia/reperfusion and HgCl2 will be used to generate acute kidney injury model. GFR and RBF will be determined with bolus FITC-inulin and PAH injection before and 1, 3 and 7 days after the injury. Right after each GFR or RBF measurement, MAG3 SPECT will be performed on these mice (before and 1, 3 and 7 days after injury). Peak%ID (percentage of kidney peak activity in injected dose), time to peak, Peak:10 min ratio, %ID(10 – 40 s) and MAG3 clearance will be calculated. In another set of mice, three mice will be sacrificed at each time point after clearance experiment and MAG3 SPECT, and kidney pathology will be examined. The correlation of the MAG3 SPECT indices with GFR, RBF and renal pathology will be analyzed. This study will determine the potential of MAG3 SPECT imaging as a non-invasive approach to detect tissue damage in mouse kidneys during the progression of disease models.

(Additional Developments in MicroSPECT Imaging)
Since the delivery of the NanoSPECT imaging system in August 2007 there has been a considerable effort focused on developing protocols and methods that enable reproducible, quantitative studies to be performed on a routine basis. Determination of the quantitative accuracy of imaging results for each radionuclide of interest to investigators will be established, first by comparison of image data for test phantoms to well counter data, and then in initial animal studies by comparison of image data to post-mortem counting of tissue samples. The possibility of performing dual-isotope studies using simultaneous application is something we are eager to explore, given the widespread interest in multi-modal, multi-parametric imaging. To establish the accuracy of dual-isotope images in estimating the activity distribution for each radiotracer, studies will be done to compare dual-isotope image data to data acquired for each radiotracer separately to investigate any errors or bias introduced by cross-contamination of one gamma-ray into the other’s energy window. Another area to be explored is the dynamic imaging capability, where it will be necessary to establish for each radiotracer of interest whether satisfactory image quality can be obtained for a reasonable injected dose with sufficiently short time intervals for the kinetics to be followed.
Under a separate R21/R33 grant from NIBIB, Dr. Todd Peterson is developing sub-millimeter imaging capabilities through the use of silicon double-sided strip detectors. He is also conducting research utilizing the modular scintillation camera technology developed at the University of Arizona. One current pursuit is the development of a camera head combining these two types of detectors behind a common aperture. This hybrid system could be used to image 123I-labeled tracers (the scintillators detecting the 159 keV gamma ray, and the silicon detectors the x-ray emissions between 27 and 32 keV) with a unique combination of sensitivity and resolution. Once a prototype system is available, it will be made available to VKDC investigators.

Publications for SPECT/PET (20)

Roberts J, Chen B, Curtis LM, Agarwal A, Sanders PW, Zinn KR. Detection of early changes in renal function using 99mTc-MAG3 imaging in a murine model of ischemia-reperfusion injury. Am J Physiol Renal Physiol (2007) 293:F1408-12
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Accurate determination of renal function in mice is a major impediment to the use of murine models in acute kidney injury. The purpose of this study was to determine whether early changes in renal function could be detected using dynamic gamma camera imaging in a mouse model of ischemia-reperfusion (I/R) injury. C57BL/6 mice (n = 5/group) underwent a right nephrectomy, followed by either 30 min of I/R injury or sham surgery of the remaining kidney. Dynamic renal studies (21 min, 10 s/frame) were conducted before surgery (baseline) and at 5, 24, and 48 h by injection of (99m)Tc-mercaptoacetyltriglycine (MAG3; approximately 1.0 mCi/mouse) via the tail vein. The percentage of injected dose (%ID) in the kidney was calculated for each 10-s interval after MAG3 injection, using standard region of interest analyses. A defect in renal function in I/R-treated mice was detected as early as 5 h after surgery compared with sham-treated mice, identified by the increased %ID (at peak) in the I/R-treated kidneys at 100 s (P < 0.01) that remained significantly higher than sham-treated mice for the duration of the scan until 600 s (P < 0.05). At 48 h, the renal scan demonstrated functional renal recovery of the I/R mice and was comparable to sham-treated mice. Our study shows that using dynamic imaging, renal dysfunction can be detected and quantified reliably as early as 5 h after I/R insult, allowing for evaluation of early treatment interventions.

Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol (2006) 17:17-25
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Recent studies emphasize the role of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal failure. When advanced, tubulointerstitial damage is associated with the loss of peritubular capillaries. Associated interstitial fibrosis impairs oxygen diffusion and supply to tubular and interstitial cells. Hypoxia of tubular cells leads to apoptosis or epithelial-mesenchymal transdifferentiation. This in turn exacerbates fibrosis of the kidney and subsequent chronic hypoxia, setting in train a vicious cycle whose end point is ESRD. A number of mechanisms that induce tubulointerstitial hypoxia at an early stage have been identified. Glomerular injury and vasoconstriction of efferent arterioles as a result of imbalances in vasoactive substances decrease postglomerular peritubular capillary blood flow. Angiotensin II not only constricts efferent arterioles but, via its induction of oxidative stress, also hampers the efficient utilization of oxygen in tubular cells. Relative hypoxia in the kidney also results from increased metabolic demand in tubular cells. Furthermore, renal anemia hinders oxygen delivery. These factors can affect the kidney before the appearance of significant pathologic changes in the vasculature and predispose the kidney to tubulointerstitial injury. Therapeutic approaches that target the chronic hypoxia should prove effective against a broad range of renal diseases. Current modalities include the improvement of anemia with erythropoietin, the preservation of peritubular capillary blood flow by blockade of the renin-angiotensin system, and the use of antioxidants. Recent studies have elucidated the mechanism of hypoxia-induced transcription, namely that prolyl hydroxylase regulates hypoxia-inducible factor. This has given hope for the development of novel therapeutic approaches against this final common pathway.

Eschmann SM, Paulsen F, Reimold M, Dittmann H, Welz S, Reischl G, Machulla HJ, Bares R. Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy. J Nucl Med (2005) 46:253-60
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In radiotherapy of head and neck cancer (HNC) and non-small cell lung cancer (NSCLC), hypoxia is known to be an important prognostic factor for long-term survival and local tumor control. The PET tracer (18)F-fluoromisonidazole (FMISO) allows noninvasive assessment of tumor hypoxia. This study analyzed whether FMISO PET could predict tumor recurrence after radiotherapy. METHODS: Forty patients with advanced HNC (n = 26) or NSCLC (n = 14) were studied before curative radiotherapy. Dynamic (0-15 min) and static PET scans were acquired up to 4 h after injection of 400 MBq of FMISO. Standardized uptake values (SUVs) and ratios to reference tissues (mediastinum or muscle) were calculated. In addition, time-activity curves up to 14 min after injection were classified visually. PET data were correlated with clinical follow-up data (presence or absence of local recurrence within 1 y), which were available for 21 patients. RESULTS: For HNC, patients with local recurrence could be separated from disease-free patients by SUV 4 h after injection (all recurrences had an SUV > 2). For NSCLC, no such correlation was observed. The tumor-to-muscle ratios (T/Mu) and tumor-to-mediastinum ratios (T/Me) at 4 h after injection correlated with the risk of relapse in both tumor entities: All patients with a T/Me greater than 2.0 (NSCLC, n = 5) or with a T/Mu greater than 1.6 (HNC, n = 5) presented with tumor recurrence, whereas only 3 of the remaining 11 patients experienced recurrence (27%). Qualitative analysis of time-activity curves for 37 patients revealed 3 curve types (rapid washout, n = 9; intermediate [delayed washout], n = 12; and accumulation, n = 16). Eighteen patients categorized by curve type could be followed up: In 5 of 6 patients with an accumulation curve, disease recurred locally within 1 y, compared with 5 of 8 patients with a delayed-washout curve and 0 of 4 with a rapid-washout curve. CONCLUSION: Our results indicate that outcome after radiotherapy can be predicted on the basis of kinetic behavior of FMISO in tumor tissue. An accumulation-type curve, high SUV, and high T/Mu and T/Me at 4 h after injection are highly suggestive of an incomplete response to treatment and might be used to select patients for intensified therapy protocols.

Dehdashti F, Mintun MA, Lewis JS, Bradley J, Govindan R, Laforest R, Welch MJ, Siegel BA. In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM. Eur J Nucl Med Mol Imaging (2003) 30:844-50
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Tumor hypoxia is recognized as an important determinant of response to therapy. In this study we investigated the feasibility of clinical imaging with copper-60 diacetyl-bis( N(4)-methylthiosemicarbazone) ((60)Cu-ATSM) in patients with non-small-cell lung cancer (NSCLC) and also assessed whether pretreatment tumor uptake of (60)Cu-ATSM predicts tumor responsiveness to therapy. Nineteen patients with biopsy-proved NSCLC were studied by positron emission tomography (PET) with (60)Cu-ATSM before initiation of therapy. (60)Cu-ATSM uptake was evaluated semiquantitatively by determining the tumor-to-muscle activity ratio (T/M). All patients also underwent PET with fluorine-18 fluorodeoxyglucose (FDG) prior to institution of therapy. The PET results were correlated with follow-up evaluation (2-46 months). It was demonstrated that PET imaging with (60)Cu-ATSM in patients with NCSLC is feasible. The tumor of one patient had no discernible (60)Cu-ATSM uptake, whereas the tumor uptake in the remaining patients was variable, as expected. Response was evaluated in 14 patients; the mean T/M for (60)Cu-ATSM was significantly lower in responders (1.5+/-0.4) than in nonresponders (3.4+/-0.8) (P=0.002). However, the mean SUV for (60)Cu-ATSM was not significantly different in responders (2.8+/-1.1) and nonresponders (3.5+/-1.0) ( P=0.2). An arbitrarily selected T/M threshold of 3.0 discriminated those likely to respond to therapy: all eight responders had a T/M <3.0 and all six nonresponders had a T/M > or =3.0. Tumor SUV for FDG was not significantly different in responders and nonresponders (P=0.7) and did not correlate with (60)Cu-ATSM uptake (r=0.04; P=0.9). (60)Cu-ATSM-PET can be readily performed in patients with NSCLC and the tumor uptake of (60)Cu-ATSM reveals clinically unique information about tumor oxygenation that is predictive of tumor response to therapy.

Dehdashti F, Grigsby PW, Mintun MA, Lewis JS, Siegel BA, Welch MJ. Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response-a preliminary report. Int J Radiat Oncol Biol Phys (2003) 55:1233-8
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PURPOSE: Tumor hypoxia is associated with poor response to therapy. We have investigated whether pretreatment tumor hypoxia assessed by positron emission tomography (PET) with Cu-60 diacetyl-bis(N(4)-methylthiosemicarbazone) ((60)Cu-ATSM) predicts responsiveness to subsequent therapy in cervical cancer. METHODS AND MATERIALS: Fourteen patients with biopsy-proved cervical cancer were studied by PET with (60)Cu-ATSM before initiation of radiotherapy and chemotherapy. (60)Cu-ATSM uptake was evaluated semiquantitatively by determining the tumor-to-muscle activity ratio (T/M) and peak slope index of tumor tracer uptake. All patients also underwent clinical PET with F-18 fluorodeoxyglucose (FDG) before institution of therapy. The PET results were correlated with follow-up evaluation (14-24 months). RESULTS: Tumor uptake of (60)Cu-ATSM was inversely related to progression-free survival and overall survival (log-rank p = 0.0005 and p = 0.015, respectively). An arbitrarily selected T/M threshold of 3.5 discriminated those likely to develop recurrence; 6 of 9 patients with normoxic tumors (T/M < 3.5) are free of disease at last follow-up, whereas all of 5 patients with hypoxic tumors (T/M > 3.5) have already developed recurrence. Similar discrimination was achieved with the peak slope index. The frequency of locoregional nodal metastasis was greater in hypoxic tumors (p = 0.03). Tumor FDG uptake did not correlate with (60)Cu-ATSM uptake (r = 0.04; p = 0.80), and there was no significant difference in tumor FDG uptake between patients with hypoxic tumors and those with normoxic tumors. CONCLUSION: (60)Cu-ATSM-PET in patients with cervical cancer revealed clinically relevant information about tumor oxygenation that was predictive of tumor behavior and response to therapy in this small study.

Piepsz A. Radionuclide studies in paediatric nephro-urology. Eur J Radiol (2002) 43:146-53
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The main tool of radionuclide techniques applied to paediatric uro-nephrology is the quantitation of function, which is an information not easily obtained by other diagnostic modalities. The radiation burden is low. Drug sedation is only rarely needed, whatever the age of the patient. Accurate determination of glomerular filtration rate can be obtained by means of an intravenous injection of Cr-51 EDTA and one or two blood samples. Tc-99m DMSA scintigraphy is an accurate method for evaluation of regional cortical impairment during acute pyelonephritis and later on, for detection of permanent scarring. Tc-99m MAG3 renography is nowadays a well-standardized method for accurate estimation of the split renal function and of renal drainage with or without furosemide challenge. This technique is particularly indicated in unior bilateral uropathies with or without renal and/or ureteral dilatation. Direct and indirect radionuclide cystography are two alternative modalities for X-ray MCUG. Their relative place in the strategy of management of vesicoureteral reflux is discussed.

Bocher M, Shrem Y, Tappiser A, Klein M, Schechter D, Taylor A Jr, Chisin R. Tc-99m mercaptoacetyltriglycine clearance: comparison of camera-assisted methods. Clin Nucl Med (2001) 26:745-50
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PURPOSE: To compare the accuracy of three camera-assisted methods for the measurement of Tc-99m mercaptoacetyltriglycine (MAG3) clearance. MATERIALS AND METHODS: MAG3 renal scintigraphy was performed in 21 adults with different degrees of renal function. Posterior views were obtained that included the heart and the kidneys in the camera field of view. The syringe for injection was imaged before and after injection. Blood samples were drawn 24 and 43 minutes after injection and plasma radioactivity was measured. Three camera-assisted techniques to measure MAG3 clearance were tested: 1) Biexponential fitting of the left ventricular curve, normalized to plasma activity at 24 minutes; 2) calculation of clearance by relating the integral of the plasma curve (normalized to plasma activity) to the kidney activity using the Rutland-Patlak space method; and 3) a regression equation measuring clearance from the percentage of the injected dose accumulating in the kidneys during the 1to 2.5-minute period. The camera-assisted clearances were compared with the single-sample MAG3 clearances calculated using the Russell equation. Linear regression analysis was used to measure the correlation between the camera-based methods and the single-sample techniques. RESULTS: Correlation with r > 0.900 was found for all three techniques. The difference in correlation coefficients between the three methods was not significant; however, the regression line of method 3 was significantly closer to the line of identity (P = 0.005). CONCLUSION: Method 3 most closely fits the line of identity and is probably the most practical because no blood sample is needed.

Lewis JS, McCarthy DW, McCarthy TJ, Fujibayashi Y, Welch MJ. Evaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor model. J Nucl Med (1999) 40:177-83
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We have evaluated Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM), an effective marker for the delineation of hypoxic but viable tissue, in vitro in the EMT6 carcinoma cell line under varying degrees of hypoxia and compared it with the flow tracer 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) and the hypoxic tracer 18F-fluoromisonidazole (MISO). We have also compared the uptake of Cu-ATSM and Cu-PTSM in vivo and ex vivo in a murine animal model bearing the EMT6 tumor. METHODS: Uptake of 64Cu-ATSM, 64Cu-PTSM and 18F-MISO in vitro into EMT6 cells was investigated at the dissolved oxygen concentrations of 0, 1 x 10(3), 5 x 10(3), 5 x 10(4) and 2 x 10(5) ppm. Biodistribution performed at 1, 5, 10, 20 and 40 min compared 64Cu-ATSM with 64Cu-PTSM in BALB/c mice bearing EMT6 tumors. To determine long-term retention of 64Cu-ATSM, biodistribution was also performed at 1, 2 and 4 h. Ex vivo autoradiography of tumor slices after co-injection of 60Cu-PTSM (60Cu, T1/2 = 23.7 min) and 64Cu-ATSM (64Cu, t1/2 = 12.7 h) into the same animal was performed. RESULTS: After 1 h, 64Cu-ATSM was taken up by EMT6 cells: 90% at 0 ppm, 77% at 1 x 10(3) ppm, 38% at 5 x 10(3) ppm, 35% at 5 x 10(4) ppm and 31% at 2 x 10(5) ppm. 18F-MISO also showed oxygen concentration dependent uptake, but with lower percentages than 64Cu-ATSM. 64Cu-PTSM showed 83%-85% uptake into the cells after 1 h, independent of oxygen concentration. Biodistribution data of 64Cu-ATSM and 64Cu-PTSM showed optimal tumor uptake after 5 and 10 min, respectively (0.76% injected dose (ID)/organ for 64Cu-ATSM and 1.11%ID/organ for 64Cu-PTSM). Ex vivo imaging experiments showed 60Cu-PTSM uniform throughout the EMT6 tumor, but heterogeneous uptake of 64Cu-ATSM, indicative of selective trapping of 64Cu-ATSM into the hypoxic tumor cells. CONCLUSION: Cu-ATSM exhibits selectivity for hypoxic tumor tissue both in vivo and in vitro and may provide a successful diagnostic modality for the detection of tumor ischemia.

Russell CD, Dubovsky EV, Taylor AT Jr. Prediction of urinary excretion of technetium-99m-MAG3. J Nucl Med (1998) 39:1257-9
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The urinary excretion of 99mTc-mercaptotriacetylglycine (MAG3), like that of 131I-orthoiodohippurate (OIH), can be used to identify acute renal transplant rejection and measure its severity. This parameter is often quantitated as the excretory index (observed excretion/predicted excretion). A new method for predicting the urinary excretion of 99mTc-MAG3 is presented. METHODS: The expected excretion was calculated from multisample plasma time-activity curves in 122 subjects, with correction for the first pass of the initial bolus. The resulting formula was tested prospectively against actual urine measurements in an additional 466 subjects. RESULTS: Least-squares fitting led to the following equation: Predicted excretion = 0.79(1-exp(-0.0066CMAG3), with residual s.d. 0.06, where CMAG3 is MAG3 clearance in ml/min and the predicted excretion is expressed as a fraction of the administered dose. Tested prospectively in the additional 466 subjects, the s.d. was 0.09. CONCLUSION: A new formula to predict the urinary excretion of 99mTc-MAG3 has been developed and prospectively validated. Based on our data, the normal range for the excretory index using MAG3 is the same as that of 131I-OIH, 0.8-1.2.

Rasey JS, Koh WJ, Evans ML, Peterson LM, Lewellen TK, Graham MM, Krohn KA. Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. Int J Radiat Oncol Biol Phys (1996) 36:417-28
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PURPOSE: To assess pretreatment hypoxia in a variety of tumors using positron emission tomography (PET) after injection of the hypoxia-binding radiopharmaceutical [18F]fluoromisonidazole ([18F]FMISO). METHODS AND MATERIALS: Tumor fractional hypoxic volume (FHV) was determined in 21 nonsmall cell lung cancer patients, 7 head and neck cancer patients, 4 prostate cancer patients, and 5 patients with other malignancies by quantitative PET imaging after injection of [18F]FMISO (0.1 mCi/kg). The FHV was defined as the proportion of pixels in the imaged tumor volume with a tissue:blood [18F] activity ratio > or = 1.4 at 120-160 min postinjection. A FHV > 0 was taken as evidence for tumor hypoxia. RESULTS: Hypoxia was observed in 36 of 37 tumors studied with FMISO PET imaging; FHVs ranged from 0 to 94.7%. In nonsmall cell lung cancers (n = 21), the median FHV was 47.6% and the range, 1.3 to 94.7%. There was no correlation between tumor size and FHV. In the seven head and neck carcinomas, the median FHV was 8.8%, with a range from 0.2 to 18.9%. In the group of four prostate cancers, the median and range were 18.2% and 0 to 93.9%, while in a group of five tumors of different types the median FHV was 55.2% (range: 21.4 to 85.8%). CONCLUSIONS: Hypoxia was present in 97% of the tumors studied and the extent of hypoxia varied markedly between tumors in the same site or of the same histology. Hypoxia also was distributed heterogeneously between regions within a single tumor. These results are consistent with O2 electrode measures with other types of human tumors. The intraand intertumor variability indicate the importance of making oxygenation measures in individual tumors and the necessity to sample as much of the tumor volume as possible.

Russell CD, Taylor AT, Dubovsky EV. Measurement of renal function with technetium-99m-MAG3 in children and adults. J Nucl Med (1996) 37:588-93
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A single-injection, single-sample procedure for measuring 99mTc-MAG3 clearance is presented that incorporates scaling for patient size and is valid for both children and adults. METHODS: The procedure is based on an empirical formula in which all measurements are expressed in dimensionless combinations. The formula was obtained by fitting data collected from 122 adults and 80 children at several centers. RESULTS: All results were scaled to standard adult surface area and are presented in units of ml/min/1.73 m2. For adult subjects, the residual standard deviation (r.s.d.) calculated from a single sample at 45 min was found to be 23, using the plasma clearance calculated from a multi-sample clearance curve as a reference. This did not differ significantly from the value of 22 obtained with our previous formula, which was valid for adults only. For pediatric subjects, an r.s.d. of 24 was calculated by the new formula from a single sample at 35 min; a comparable value of 33 was found using a pediatric formula previously published. CONCLUSION: The new clearance formula is recommended as a replacement for the formula we previously published, since it is based on a larger and more diverse subject population, and since it now holds for children as well, with no loss of accuracy for adult subjects.

Taylor A Jr, Clark S, Ball T. Comparison of Tc-99m MAG3 and Tc-99m DTPA scintigraphy in neonates. Clin Nucl Med (1994) 19:575-80
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Tc-99m MAG3 scans were obtained in two neonates in whom previous Tc-99m DTPA scans had been interpreted as showing possible obstruction. In both patients, Tc-99m MAG3 provided superior diagnostic images and allowed obstruction to be excluded. The favorable dosimetry of MAG3, coupled with the fact that its clearance is two to three times higher than that of DTPA, makes MAG3 an excellent radiopharmaceutical for pediatric patients, particularly in those patients with impaired renal function and possible obstruction.

Muller-Suur R, Muller-Suur C. Renal and extrarenal handling of a new imaging compound (99m-Tc-MAG-3) in the rat. Eur J Nucl Med (1986) 12:438-42
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Taylor A Jr, Eshima D, Fritzberg AR, Christian PE, Kasina S. Comparison of iodine-131 OIH and technetium-99m MAG3 renal imaging in volunteers. J Nucl Med (1986) 27:795-803
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Fritzberg AR, Kasina S, Eshima D, Johnson DL. Synthesis and biological evaluation of technetium-99m MAG3 as a hippuran replacement. J Nucl Med (1986) 27:111-6
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Raleigh JA, Koch CJ. Importance of thiols in the reductive binding of 2-nitroimidazoles to macromolecules. Biochem Pharmacol (1990) 40:2457-64
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Reductive activation of 2-nitroimidazoles in the presence of bovine serum albumin (BSA) led to binding of the nitroheterocycles to the protein. The binding was most efficient to BSA in which protein disulfides had been reduced to thiol groups. Protein thiols were at least twenty times more efficient than other protein, RNA or DNA nucleophiles in binding the reductively-activated nitroheterocycles. This result is of practical importance in the development of immunoassays for 2-nitroimidazoles as hypoxia markers in normal and tumor tissue.

Muller-Suur C, Muller-Suur R. Handling of 99mTc-MAG3 in the kidney. Contrib Nephrol (1990) 79:17-20
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Vaupel P, Schlenger K, Knoop C, Hockel M. Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res (1991) 51:3316-22
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Direct oxygen partial pressure (pO2) readings in breast cancers, in fibrocystic disease, and in the normal breast have been obtained using a novel technique which allows for the systematic evaluation of the oxygenation status as a function of pathological staging and histological grading. Measurements were performed in awake preand postmenopausal patients with well-defined arterial blood gas status. The measuring procedure encompasses a computerized electrode movement in the tissue which avoids significant compression artifacts and allows routine measurement in human tumors before, during, and after treatment. Using this reliable technique, pO2 measurements in the normal breast and in fibrocystic disease resulted in oxygenation patterns which were characteristic for normal, adequately supplied tissues. The median pO2 values were 65 and 67 mm Hg, respectively, with no pO2 readings below 12.5 mm Hg in the normal breast, and less than or equal to 5 mm Hg in fibrocystic disease, respectively. In contrast, in breast cancers the median pO2 value was 30 mm Hg (pooled data for pathological stages T1-T4). To date, 6 of 15 breast cancers exhibited pO2 values between zero and 2.5 mm Hg, i.e., tissue areas with less than half-maximum radiosensitivity. The oxygenation pattern in breast cancers and the occurrence of hypoxia and/or anoxia did not correlate with either the pathological stages and histological grades or with a series of clinically relevant parameters. No significant differences were found between preand postmenopausal tumors and between lobular and ductal carcinomas. Tumor-to-tumor variability in the oxygenation pattern was more pronounced than intra-tumor heterogeneity. pO2 variations within a tumor cannot be predicted, e.g., as a function of the measuring site (tumor center versus periphery).

Cline JM, Thrall DE, Page RL, Franko AJ, Raleigh JA. Immunohistochemical detection of a hypoxia marker in spontaneous canine tumours. Br J Cancer (1990) 62:925-31
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An immunoperoxidase technique has been used to detect the in vivo binding of a 2-nitroimidazole hypoxia marker in histochemical sections of a variety of excised canine tumours. The binding occurred 10-12 cell diameters away from tumour blood vessels, consistent with the expected location of hypoxic cells in tissues in which oxygen concentration gradients are established by diffusion. Hypoxic fractions ranging from 4 to 13% have been estimated on the basis of morphometric analysis of multiple tumour sections. The binding of the marker was restricted to the cytoplasm of the cells. The marker appeared in regions adjacent to necrosis but also in regions free of necrosis. As in earlier autoradiography studies, binding was occasionally observed in cells adjacent to tumour blood vessels. Generally, binding to normal tissues was not observed. However, binding to smooth muscle cells surrounding arterioles in some sections of normal tissue and tumour tissue was observed.

Martin GV, Caldwell JH, Graham MM, Grierson JR, Kroll K, Cowan MJ, Lewellen TK, Rasey JS, Casciari JJ, Krohn KA. Noninvasive detection of hypoxic myocardium using fluorine-18-fluoromisonidazole and positron emission tomography. J Nucl Med (1992) 33:2202-8
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Fluoromisonidazole (FMISO) is metabolically trapped in viable cells as a function of reduced cellular pO2. Therefore [18F]-FMISO is potentially useful for evaluating patients with hypoxic but viable myocardium. The goal of this study was to investigate [18F]FMISO uptake in ischemic myocardium non-invasively using positron emission tomography (PET). Studies were performed in 10 open-chest dogs subjected to either complete (Group 1, n = 5) or partial (Group 2, n = 5) occlusion of the left anterior descending coronary artery. The tracer was administered by intravenous bolus following the onset of ischemia and serial PET images were acquired for the next 4 hr. In Group 1, viability was assessed using histochemical staining (nitroblue tetrazolium, NBT) and 99mTc-pyrophosphate (Tc-PYP). In Group 2, viability was assessed using measurements of regional wall motion, histochemical staining and histology (two animals). In each study, PET images obtained at times between 2 and 4 hr postinjection showed specific enhancement of tracer activity in the distal anterior wall and apex of the left ventricle. At 4 hr, the tissue-to-blood pool count ratio was significantly higher in ischemic regions; 1.8 +/0.4 for Group 1 and 1.6 +/0.2 for Group 2 versus 1.0 +/0.1 in nonischemic regions. Postmortem tissue sampling of Group 1 hearts showed significant FMISO retention in samples without evidence for infarction, either by NBT or Tc-PYP deposition, as well as in more severely ischemic regions. In Group 2 animals, FMISO was retained in myocardial regions with reduced blood flow (microspheres), which exhibited improved contraction following reperfusion. We conclude that PET imaging of [18F]FMISO is a promising technique for the noninvasive identification of viable hypoxic myocardium.

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