An integrative latent class model of heterogeneous data modalities for diagnosing kidney obstruction.

Radionuclide imaging plays a critical role in the diagnosis and management of kidney obstruction. However, most practicing radiologists in US hospitals have insufficient time and resources to acquire training and experience needed to interpret radionuclide images, leading to increased diagnostic errors. To tackle this problem, Emory University embarked on a study that aims to develop a computer-assisted diagnostic (CAD) tool for kidney obstruction by mining and analyzing patient data comprised of renogram curves, ordinal expert ratings on the obstruction status, pharmacokinetic variables, and demographic information. The major challenges here are the heterogeneity in data modes and the lack of gold standard for determining kidney obstruction. In this article, we develop a statistically principled CAD tool based on an integrative latent class model that leverages heterogeneous data modalities available for each patient to provide accurate prediction of kidney obstruction. Our integrative model consists of three sub-models (multilevel functional latent factor regression model, probit scalar-on-function regression model, and Gaussian mixture model), each of which is tailored to the specific data mode and depends on the unknown obstruction status (latent class). An efficient MCMC algorithm is developed to train the model and predict kidney obstruction with associated uncertainty. Extensive simulations are conducted to evaluate the performance of the proposed method. An application to an Emory renal study demonstrates the usefulness of our model as a CAD tool for kidney obstruction.

Computer assisted interpretation of Tc-99m mercaptoacetyltriglycine diuretic scintigraphy enhances resident performance.

OBJECTIVE: iRENEX is a software module that incorporates scintigraphic and clinical data to interpret 99m Tc- mercaptoacetyltriglycine (MAG3) diuretic studies and provide reasons for their conclusions. Our objectives were to compare iRENEX interpretations with those of expert physicians, use iRENEX to evaluate resident performance and determine if iRENEX could improve the diagnostic accuracy of experienced residents. METHODS: Baseline and furosemide 99m Tc-MAG3 acquisitions of 50 patients with suspected obstruction (mean age ± SD, 58.7 ±â€…15.8 years, 60% female) were randomly selected from an archived database and independently interpreted by iRENEX, three expert readers and four nuclear medicine residents with one full year of residency. All raters had access to scintigraphic data and a text file containing clinical information and scored each kidney on a scale from +1.0 to -1.0. Scores ≥0.20 represented obstruction with higher scores indicating greater confidence. Scores +0.19 to -0.19 were indeterminate; scores ≤-0.20 indicated no obstruction. Several months later, residents reinterpreted the studies with access to iRENEX. Receiver operating characteristic (ROC) analysis and concordance correlation coefficient (CCC) quantified agreement. RESULTS: The CCC among experts was higher than that among residents, 0.84, versus 0.39, respectively, P  < 0.001. When residents reinterpreted the studies with iRENEX, their CCC improved from 0.39 to 0.73, P  < 0.001. ROC analysis showed significant improvement in the ability of residents to distinguish between obstructed and non-obstructed kidneys using iRENEX ( P  = 0.036). CONCLUSION: iRENEX interpretations were comparable to those of experts. iRENEX reduced interobserver variability among experienced residents and led to better agreement between resident and expert interpretations.

Genomic divergence, local adaptation, and complex demographic history may inform management of a popular sportfish species complex.

The Neosho Bass (Micropterus velox), a former subspecies of the keystone top-predator and globally popular Smallmouth Bass (M. dolomieu), is endemic and narrowly restricted to small, clear streams of the Arkansas River Basin in the Central Interior Highlands (CIH) ecoregion, USA. Previous studies have detected some morphological, genetic, and genomic differentiation between the Neosho and Smallmouth Basses; however, the extent of neutral and adaptive divergence and patterns of intraspecific diversity are poorly understood. Furthermore, lineage diversification has likely been impacted by gene flow in some Neosho populations, which may be due to a combination of natural biogeographic processes and anthropogenic introductions. We assessed: (1) lineage divergence, (2) local directional selection (adaptive divergence), and (3) demographic history among Smallmouth Bass populations in the CIH using population genomic analyses of 50,828 single-nucleotide polymorphisms (SNPs) obtained through ddRAD-seq. Neosho and Smallmouth Bass formed monophyletic clades with 100% bootstrap support. We identified two major lineages within each species. We discovered six Neosho Bass populations (two nonadmixed and four admixed) and three nonadmixed Smallmouth Bass populations. We detected 29 SNPs putatively under directional selection in the Neosho range, suggesting populations may be locally adapted. Two populations were admixed via recent asymmetric secondary contact, perhaps after anthropogenic introduction. Two other populations were likely admixed via combinations of ancient and recent processes. These species comprise independently evolving lineages, some having experienced historical and natural admixture. These results may be critical for management of Neosho Bass as a distinct species and may aid in the conservation of other species with complex biogeographic histories.

Phylogenomics and species delimitation of the economically important Black Basses (Micropterus).

Informed management and conservation efforts are vital to sustainable recreational fishing and biodiversity conservation. Because the taxonomic rank of species is important in conservation and management strategies, success of these efforts depends on accurate species delimitation. The Black Basses (Micropterus) are an iconic lineage of freshwater fishes that include some of the world's most popular species for recreational fishing and world's most invasive species. Despite their popularity, previous studies to delimit species and lineages in Micropterus suffer from insufficient geographic coverage and uninformative molecular markers. Our phylogenomic analyses of ddRAD data result in the delimitation of 19 species of Micropterus, which includes 14 described species, the undescribed but well-known Altamaha, Bartram's, and Choctaw basses, and two additional undescribed species currently classified as Smallmouth Bass (M. dolomieu). We provide a revised delimitation of species in the Largemouth Bass complex that necessitates a change in scientific nomenclature: Micropterus salmoides is retained for the Florida Bass and Micropterus nigricans is elevated from synonymy for the Largemouth Bass. The new understanding of diversity, distribution, and systematics of Black Basses will serve as important basis for the management and conservation of this charismatic and economically important clade of fishes.

Head to head comparison of [99mTc]Tc(CO)3(NTA) and [99mTc]Tc-MAG3 in patients with suspected obstruction.

PURPOSE: 99mTc-tricarbonyl-nitrilotriacetic acid, [99mTc]Tc(CO)3(NTA), is a new 99mTc-renal radiopharmaceutical with a clearance equal to that of 131I-ortho-iodohippuran, [131I]I-OIH. Our purpose was to compare the performance of [99mTc]Tc(CO)3(NTA) and [99mTc]Tc-MAG3 in patients with suspected obstruction. METHODS: [99mTc]Tc(CO)3(NTA) was prepared with commercially available NTA ligand and CRS Isolink kit, and isolated by HPLC. Eighteen adult patients referred for diuretic renography received an intravenous injection of approximately 40 mg of furosemide 15 min prior to either [99mTc]Tc(CO)3(NTA) or [99mTc]Tc-MAG3 (mean activity of 47 ± 4.4 MBq). Data were acquired for 24 min followed by an anterior image of the liver and gall bladder and a measure of voided volume. Patients received a second furosemide injection equal to one third of the original dose followed fifteen minutes later by administration of the alternate tracer, mean activity of 320 ± 34 MBq. Clearances were measured using a camera-based technique. RESULTS: The clearance of NTA was greater than that of MAG3, 331 ± 146 versus 271 ± 105 mL/min/1.73 m2, respectively, p < 0.0001. The kidney to background ratio for NTA was greater than that of MAG3 for both left and right kidneys, p < 0.001; the 20 min/maximum count ratio was significantly less, p < 0.0001. There was no significant difference in the voiding volumes following NTA and MAG3 administration, 598 ± 237 mL versus 498 ± 170 mL, respectively, p = 0.07. Gall bladder activity was not observed with NTA but was present in 6/17 MAG3 studies. Images and renogram curves were comparable except for two patients where the NTA study excluded obstruction but the MAG3 study suggested an indeterminate or obstructed kidney. CONCLUSIONS: Unlike MAG3, NTA is not eliminated via the hepatobiliary track. Moreover, NTA has a higher kidney to background ratio and more rapid clearance than MAG3. These advantages should allow more robust camera-based clearance measurements and may lead to better discrimination between obstructed and non-obstructed kidneys.

Spatial sampling bias and model complexity in stream-based species distribution models: A case study of Paddlefish (Polyodon spathula) in the Arkansas River basin, USA.

Leveraging existing presence records and geospatial datasets, species distribution modeling has been widely applied to informing species conservation and restoration efforts. Maxent is one of the most popular modeling algorithms, yet recent research has demonstrated Maxent models are vulnerable to prediction errors related to spatial sampling bias and model complexity. Despite elevated rates of biodiversity imperilment in stream ecosystems, the application of Maxent models to stream networks has lagged, as has the availability of tools to address potential sources of error and calculate model evaluation metrics when modeling in nonraster environments (such as stream networks). Herein, we use Maxent and customized R code to estimate the potential distribution of paddlefish (Polyodon spathula) at a stream-segment level within the Arkansas River basin, USA, while accounting for potential spatial sampling bias and model complexity. Filtering the presence data appeared to adequately remove an eastward, large-river sampling bias that was evident within the unfiltered presence dataset. In particular, our novel riverscape filter provided a repeatable means of obtaining a relatively even coverage of presence data among watersheds and streams of varying sizes. The greatest differences in estimated distributions were observed among models constructed with default versus AICC-selected parameterization. Although all models had similarly high performance and evaluation metrics, the AICC-selected models were more inclusive of westward-situated and smaller, headwater streams. Overall, our results solidified the importance of accounting for model complexity and spatial sampling bias in SDMs constructed within stream networks and provided a roadmap for future paddlefish restoration efforts in the study area.

A Bayesian Latent Class Model to Predict Kidney Obstruction in the Absence of Gold Standard.

Kidney obstruction, if untreated in a timely manner, can lead to irreversible loss of renal function. A widely used technology for evaluations of kidneys with suspected obstruction is diuresis renography. However, it is generally very challenging for radiologists who typically interpret renography data in practice to build high level of competency due to the low volume of renography studies and insufficient training. Another challenge is that there is currently no gold standard for detection of kidney obstruction. Seeking to develop a computer-aided diagnostic (CAD) tool that can assist practicing radiologists to reduce errors in the interpretation of kidney obstruction, a recent study collected data from diuresis renography, interpretations on the renography data from highly experienced nuclear medicine experts as well as clinical data. To achieve the objective, we develop a statistical model that can be used as a CAD tool for assisting radiologists in kidney interpretation. We use a Bayesian latent class modeling approach for predicting kidney obstruction through the integrative analysis of time-series renogram data, expert ratings, and clinical variables. A nonparametric Bayesian latent factor regression approach is adopted for modeling renogram curves in which the coefficients of the basis functions are parameterized via the factor loadings dependent on the latent disease status and the extended latent factors that can also adjust for clinical variables. A hierarchical probit model is used for expert ratings, allowing for training with rating data from multiple experts while predicting with at most one expert, which makes the proposed model operable in practice. An efficient MCMC algorithm is developed to train the model and predict kidney obstruction with associated uncertainty. We demonstrate the superiority of the proposed method over several existing methods through extensive simulations. Analysis of the renal study also lends support to the usefulness of our model as a CAD tool to assist less experienced radiologists in the field.

fac-99mTc/Re-tricarbonyl complexes with tridentate aminocarboxyphosphonate ligands: suitability of the phosphonate group in chelate ligand design of new imaging agents.

Ligands that coordinate via dianionic phosphonate groups have not been widely utilized in radiopharmaceuticals. N-(phosphonomethyl)iminodiacetic acid (1, PMIDA) and N-(phosphonomethyl)glycine (2, PMG) were investigated as new chelators for the 99mTc/Re-tricarbonyl "core" (fac-M(CO)3, M = 99mTc, Re) present in a major class of radiopharmaceuticals. fac-M(CO)3(PMIDA) and fac-M(CO)3(PMG) complexes were studied by HPLC and 1H/13C/31P NMR methods for M = Re (Re-1 and Re-2) and by HPLC for M = 99mTc ( 99m Tc-1 and 99m Tc-2). Re-1 and 99m Tc-1 complexes exhibit a similar pH-dependent equilibrium between geometric linkage isomers (M-1a and M-1b). However, only one isomer exists for M-2 under all conditions. Structural characterization by X-ray crystallography reveals the presence of a bond between a phosphonate oxygen and the Re(I) center in fac-Re(CO)3(PMG) (Re-2). Detailed comparisons of NMR data for Re-2 conclusively demonstrate that the phosphonate group is coordinated in Re-1b (isomer favored at high pH) but not in Re-1a, which has a dangling N-(phosphonomethyl) group. To our knowledge, Re-1b and Re-2 and their 99mTc analogs are the first well-documented examples of complexes with these metal-tricarbonyl cores having a dianionic phosphonate group directly coordinated in a fac-M(CO)3-O-P grouping. Pharmacokinetic studies using Sprague-Dawley rats reveal that 99m Tc-2 is a robust tracer. Hence, phosphonate groups should be considered in designing 99mTc and 186/188Re radiopharmaceuticals, including agents with bioactive moieties attached to dangling carboxylate or phosphonate groups.

Overall indices for assessing agreement among multiple raters.

The need to assess agreement exists in various clinical studies where quantifying inter-rater reliability is of great importance. Use of unscaled agreement indices, such as total deviation index and coverage probability (CP), is recommended for two main reasons: (i) they are intuitive in a sense that interpretations are tied to the original measurement unit; (ii) practitioners can readily determine whether the agreement is satisfactory by directly comparing the value of the index to a prespecified tolerable CP or absolute difference. However, the unscaled indices were only defined in the context of comparing two raters or multiple raters that assume homogeneity of variances across raters. In this paper, we introduce a set of overall indices based on the root mean square of pairwise differences that are unscaled and can be used to evaluate agreement among multiple raters that often exhibit heterogeneous measurement processes in practice. Furthermore, we propose another overall agreement index based on the root mean square of pairwise differences that is scaled and extends the concept of the recently proposed relative area under CP curve in the presence of multiple raters. We present the definitions of overall indices and propose inference procedures in which bootstrap methods are used for the estimation of standard errors. We assess the performance of the proposed approach and demonstrate its superiority over the existing methods when raters exhibit heterogeneous measurement processes using simulation studies. Finally, we demonstrate the application of our methods using a renal study.

The BEIR VII Estimates of Low-Dose Radiation Health Risks Are Based on Faulty Assumptions and Data Analyses: A Call for Reassessment.

The 2006 National Academy of Sciences Biologic Effects of Ionizing Radiation (BEIR) VII report is a well-recognized and frequently cited source on the legitimacy of the linear no-threshold (LNT) model-a model entailing a linear and causal relationship between ionizing radiation and human cancer risk. Linearity means that all radiation causes cancer and explicitly excludes a threshold below which radiogenic cancer risk disappears. However, the BEIR VII committee has erred in the interpretation of its selected literature; specifically, the in vitro data quoted fail to support LNT. Moreover, in vitro data cannot be considered as definitive proof of cancer development in intact organisms. This review is presented to stimulate a critical reevaluation by a BEIR VIII committee to reassess the validity, and use, of LNT and its derived policies.

Re(CO)3([18F]FEDA), a novel 18F PET renal tracer: Radiosynthesis and preclinical evaluation.

INTRODUCTION: Our previous work demonstrated that the 99mTc renal tracer, 99mTc(CO)3(FEDA) (99mTc-1), has a rapid clearance comparable in rats to that of 131I-OIH, the radioactive gold standard for the measurement of effective renal plasma flow. The uncharged fluoroethyl pendant group of 99mTc-1 provides a route to the synthesis of a structurally analogous rhenium-tricarbonyl 18F renal imaging agent, Re(CO)3([18F]FEDA) (18F-1). Our goal was to develop an efficient one-step method for the preparation of 18F-1 and to compare its pharmacokinetic properties with those of 131I-OIH in rats. METHODS: 18F-1 was prepared by the nucleophilic 18F-fluorination of its tosyl precursor. The labeled compound was isolated by HPLC and subsequently evaluated in Sprague-Dawley rats using 131I-OIH as an internal control and by dynamic PET/CT imaging. Plasma protein binding (PPB) and erythrocyte uptake (RCB) were determined and the urine was analyzed for metabolites. RESULTS: 18F-1 was efficiently prepared as a single species with high radiochemical purity (>99%) and it displayed high radiochemical stability in vitro and in vivo. PPB was 87% and RCB was 21%. Biodistribution studies confirmed rapid renal extraction and high specificity for renal excretion, comparable to that of 131I-OIH, with minimal hepatic/gastrointestinal elimination. The activity in the urine, as a percentage of 131I-OIH, was 92% and 95% at 10 and 60 min, respectively. All other organs (heart, spleen, lungs) showed a negligible tracer uptake (<0.4% ID). Dynamic microPET/CT imaging demonstrated rapid transit of 18F-1 through the kidneys and into the bladder; there was no demonstrable activity in bone verifying the absence of free [18F]fluoride. CONCLUSIONS: 18F-1 exhibited a high specificity for the kidney, rapid renal excretion comparable to that of 131I-OIH and high in vivo radiochemical stability. Not only is 18F-1 a promising PET renal tracer, but it provides a route to the development of a pair of analogous 18F/99mTc renal imaging agents with almost identical structures and comparable pharmacokinetic properties. These promising in vivo results warrant subsequent evaluation in humans.

Incorporating fragmentation and non-native species into distribution models to inform fluvial fish conservation.

Fluvial fishes face increased imperilment from anthropogenic activities, but the specific factors contributing most to range declines are often poorly understood. For example, the range of the fluvial-specialist shoal bass (Micropterus cataractae) continues to decrease, yet how perceived threats have contributed to range loss is largely unknown. We used species distribution models to determine which factors contributed most to shoal bass range loss. We estimated a potential distribution based on natural abiotic factors and a series of currently occupied distributions that incorporated variables characterizing land cover, non-native species, and river fragmentation intensity (no fragmentation, dams only, and dams and large impoundments). We allowed interspecific relationships between non-native congeners and shoal bass to vary across fragmentation intensities. Results from the potential distribution model estimated shoal bass presence throughout much of their native basin, whereas models of currently occupied distribution showed that range loss increased as fragmentation intensified. Response curves from models of currently occupied distribution indicated a potential interaction between fragmentation intensity and the relationship between shoal bass and non-native congeners, wherein non-natives may be favored at the highest fragmentation intensity. Response curves also suggested that >100 km of interconnected, free-flowing stream fragments were necessary to support shoal bass presence. Model evaluation, including an independent validation, suggested that models had favorable predictive and discriminative abilities. Similar approaches that use readily available, diverse, geospatial data sets may deliver insights into the biology and conservation needs of other fluvial species facing similar threats.

99mTc-MAG3: Image Wisely.

Purpose To determine if commonly administered doses of technetium 99m (99mTc) mertiatide (MAG3) in the range of 300-370 MBq (approximately 8-10 mCi) contribute to image interpretation and justify the resulting radiation exposure. Materials and Methods The respective institutional review boards approved this HIPAA-compliant study and waived informed consent. Baseline and furosemide 99mTc-MAG3 imaging examinations in 50 patients suspected of having renal obstruction and 48 patients suspected of having renovascular hypertension (RVH) were randomly selected from archived databases and were independently scored by three experienced readers without access to 2-second flow images. Readers were blinded to their original scores, and then they rescored each examination with access to high-activity 2-second flow images. Relative renal function was determined after a low activity (62.9 MBq ± 40.7) baseline acquisition for RVH and a high activity (303.4 MBq ± 48.1) acquisition after administration of enalaprilat. Data were analyzed by using random effects analysis of variance and mean and standard error of the mean for the difference between sets of scores and the difference between relative function measurements. Results There was no significant difference in the scores without flow images compared with blinded scores with high-activity flow images for patients suspected of having obstruction (P = .80) or RVH (P = .24). Moreover, there was no significant difference in the relative uptake measurements after administration of low and high activities (P > .99). Conclusion Administered doses of 99mTc-MAG3 in the range of 300-370 MBq (approximately 8-10 mCi) do not affect the relative function measurements or contribute to interpretation of images in patients suspected of having RVH or obstruction compared with administration of lower doses; unnecessary radiation exposure can be avoided by administering doses in the range of 37-185 MBq as recommended incurrent guidelines. © RSNA, 2017.

Monoanionic 99mTc-tricarbonyl-aminopolycarboxylate complexes with uncharged pendant groups: Radiosynthesis and evaluation as potential renal tubular tracers.

INTRODUCTION: 99mTc(CO)3-nitrilotriacetic acid, 99mTc(CO)3(NTA), is a new renal tubular agent with pharmacokinetic properties comparable to those of 131I-OIH but the clearance of 99mTc(CO)3(NTA) and 131I-OIH is still less than the clearance of PAH, the gold standard for the measurement of effective renal plasma flow. At physiological pH, dianionic 99mTc(CO)3(NTA) has a mononegative inner metal-coordination sphere and a mononegative uncoordinated carboxyl group. To evaluate alternate synthetic approaches, we assessed the importance of an uncoordinated carboxyl group, long considered essential for tubular transport, by evaluating the pharmacokinetics of three analogs with the 99mTc(CO)3(NTA) metal-coordination sphere but with uncharged pendant groups. METHODS: 99mTc(CO)3 complexes with N-(2-acetamido)iminodiacetic acid (ADA), N-(2-hydroxyethyl)iminodiacetic acid (HDA) and N-(fluoroethyl)iminodiacetic acid (FEDA) were prepared using a tricarbonyl kit and isolated by HPLC. The pharmacokinetics were evaluated in Sprague-Dawley rats, with 131I-OIH as an internal control; urine was analyzed for metabolites. Plasma protein binding and erythrocyte uptake were determined from the 10min blood samples. Re(CO)3(FEDA), the analog of 99mTc(CO)3(FEDA), was prepared and characterized. RESULTS: 99mTc(CO)3(ADA), 99mTc(CO)3(HDA) and 99mTc(CO)3(FEDA) were efficiently prepared as a single species with high radiochemical purities (>99%). These new monoanionic 99mTc(CO)3 tracers with uncharged dangling groups all showed rapid blood clearance and high specificity for renal excretion. Activity in the urine, as a percent of 131I-OIH at 10 and 60min, was 96% and 99% for ADA, 96% and 100% for HDA, and 100% and 99% for FEDA, respectively. Each new tracer was excreted unchanged in the urine. The Re(CO)3(FEDA) structure adds compelling evidence that such 99mTc(CO)3(NTA) analogs have metal-coordination spheres identical to that of 99mTc(CO)3(NTA). CONCLUSIONS: New tracers lacking the negatively charged pendant carboxyl group previously thought to be essential for rapid renal extraction, 99mTc(CO)3(ADA), 99mTc(CO)3(HDA) and 99mTc(CO)3(FEDA), exhibit pharmacokinetics in rats comparable to those of 99mTc(CO)3(NTA) and 131I-OIH. Furthermore, these encouraging results in rats warrant evaluation of this new tracer type in humans.

Structure and Properties of fac-[Re(I)(CO)3(NTA)](2-) (NTA(3-) = Trianion of Nitrilotriacetic Acid) and fac-[Re(I)(CO)3(L)](n-) Analogues Useful for Assessing the Excellent Renal Clearance of the fac-[(99m)Tc(I)(CO)3(NTA)](2-) Diagnostic Renal Agent.

We previously identified two new agents based on the [(99m)Tc(V)O](3+) core with renal clearances in human volunteers 30% higher than that of the widely used clinical tracer (99m)Tc-MAG3 (MAG3(5-) = penta-anion of mercaptoacetyltriglycine). However, renal agents with even higher clearances are needed. More recently, we changed our focus from the [(99m)Tc(V)O](3+) core to the discovery of superior tracers based on the fac-[(99m)Tc(I)(CO)3](+) core. Compared to (99m)Tc-MAG3, fac-[(99m)Tc(I)(CO)3(NTA)](2-) (NTA(3-) = trianion of nitrilotriacetic acid) holds great promise by virtue of its efficient renal clearance via tubular secretion and the absence of hepatobiliary elimination, even in patients with severely reduced renal function. We report here NMR, molecular (X-ray) structure, and solution data on fac-[Re(I)(CO)3(NTA)](2-) with a -CH2CO2(-) dangling monoanionic chain and on two fac-[Re(I)(CO)3(L)](-) analogues with either a -CH2CONH2 or a -CH2CH2OH dangling neutral chain. In these three fac-[Re(I)(CO)3(L)](n-) complexes, the fac-[Re(I)(CO)3(N(CH2CO2)2)](-) moiety is structurally similar and has similar electronic properties (as assessed by NMR data). In reported and ongoing studies, the two fac-[(99m)Tc(I)(CO)3(L)](-) analogues with these neutral dangling chains were found to have pharmacokinetic properties very similar to those of fac-[(99m)Tc(I)(CO)3(NTA)](2-). Therefore, we reach the unexpected conclusion that in fac-[(99m)Tc(I)(CO)3(L)](n-) agents, renal clearance is affected much more than anticipated by features of the core plus the chelate rings (the [(99m)Tc(I)(CO)3(N(CH2CO2)2)](-) moiety) than by the presence of a negatively charged dangling carboxylate chain.

Identification of lead compounds for (99m)Tc and (18)F GPR91 radiotracers.

To develop the first radiotracer targeting GPR91, a cell membrane-bound receptor that modulates the cellular response to hyperglycemia and hypoxia, we designed and prepared a small series of compounds based on a published series of 1,8-naphthyridines with high affinity to GPR91. Our approach provides a mechanism to incorporate radioactive atoms ((99m)Tc and (18)F) into the GPR91 pharmacophore as the final synthetic step. Pharmacological assays confirmed lead compounds for (99m)Tc and (18)F GPR91 radiotracers within the series.

Initial Evaluation of (99m)Tc(CO)3(ASMA) as a Renal Tracer in Healthy Human Volunteers.

PURPOSE: Preclinical studies in rats showed that two of (99m)Tc(CO)3(ASMA) isomers (rac- and L-ASMA) had pharmacokinetic properties equivalent to that of (131)I-OIH, the radiopharmaceutical standard for the measurement of effective renal plasma flow. The aim of this study was to evaluate the pharmacokinetics of (99m)Tc(CO)3(ASMA) isomers in healthy human subjects. METHODS: Three ASMA ligands (rac-, L- and D-ASMA) were labeled with (99m)Tc(CO)3 using an IsoLink kit (Covidien), and each formed (99m)Tc(CO)3(ASMA) tracer was co-injected with (131)I-OIH into healthy human subjects followed by sequential imaging, plasma clearance measurements and timed urine collection. Plasma protein binding, red cell uptake and percent injected dose in the urine were determined. Urine from each group of volunteers was analyzed for metabolites by HPLC. RESULTS: Image quality was excellent with all three agents. Each (99m)Tc(CO)3(ASMA) preparation was excreted unchanged in the urine. The plasma clearance ratio ((99m)Tc(CO)3(ASMA)/(131)I-OIH) was 81 ± 3 % for D-ASMA compared to only 20 ± 4 % for L-ASMA and 37 ± 7 % for rac-ASMA; the 81 % clearance ratio for D-ASMA isomer is still ∼ 30 % higher than the (99m)Tc-MAG3/(131)I-OIH clearance ratio (∼50-60 %). Red cell uptake was similar for all three tracers (6-9 %), and all tracers had a relatively rapid renal excretion; at 3 h, the (99m)Tc(CO)3(ASMA)/(131)I-OIH urine ratio was 100 ± 3 % for D-ASMA, 80 ± 2 % for L-ASMA and 88 ± 1 % for rac-ASMA. CONCLUSIONS: The renal excretion characteristics of (99m)Tc(CO)3(D-ASMA) in humans are superior to those of the other two (99m)Tc(CO)3(ASMA) isomers studied, but are still inferior to (131)I-OIH, even though there was no difference in the clearance of two of (99m)Tc(CO)3(ASMA) isomers and (131)I-OIH in rats. The work described here demonstrates the sensitivity in in vivo biological behavior of (99m)Tc(CO)3(ASMA) isomers to their subtle structural differences.