Prospective comparison of positron emission tomography (PET)/magnetic resonance and PET/computed tomography dosimetry in hepatic malignant neoplastic disease after 90Y radioembolization treatment.

Background: 90Y radioembolization is an established treatment modality for hepatic malignancies. Successful radioembolization requires optimal dose delivery to tumors while minimizing dosages to parenchyma. Post-treatment positron emission tomography (PET)/computed tomography (CT) dosimetry is the established benchmark, whereas PET/magnetic resonance (MR) is an emerging modality. The goal of this study was to assess the intermodality agreement between PET/MR and PET/CT 90Y dosimetry. Methods: In this single-institution study, 18 patients (20 treatment sessions) with a primary or metastatic hepatic malignancy underwent both PET/MR and PET/CT after 90Y radioembolization. Patients were randomized to undergo one modality first, followed by the other. The region of interest was delineated using MR images and tumor and liver dosimetry was calculated. Intermodality agreement was assessed using the Bland-Altman method. A generalized linear model was used to assess the effect of baseline variables on intermodality dose differences. Results: PET/MR underestimated tumor and liver absorbed doses when compared to PET/CT by -3.7% (P=0.042) and -5.8% (P=0.029), respectively. A coverage probability plot demonstrated that 80% and 90% of tumor dose measurements fell within intermodality differences of 11% and 18%, respectively. PET/MR underestimated tumor dose at both low (<1 GBq) and high (>3 GBq) injected activity levels (P<0.001) by -22.3 [standard deviation (SD) =13.5] and -24.3 (SD =18.7), respectively. Conclusions: Although PET/MR significantly underestimated the absorbed dose when compared to PET/CT, the intermodality agreement was high and the degree of underestimation was better than previously reported. Intermodality differences were more pronounced at low and high injected doses. Additional studies are required to assess the clinical implications of these findings.

A novel PSMA-targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11.

BACKGROUND: The current generation of radiolabeled PSMA-targeting therapeutic agents is limited by prominent salivary gland binding, which results in dose-limiting xerostomia from radiation exposure. JB-1498 is a urea-based small molecule with a highly negatively charged linker targeting prostate specific membrane antigen (PSMA). Prior work on a similar tracer with the same negatively charged linker demonstrated low normal organ/soft tissue background uptake compared to [68Ga]Ga-PSMA-11. The purpose of this study was to investigate if [68Ga]Ga-JB-1498 had reduced salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11. RESULTS: JB-1498 demonstrated high affinity for PSMA binding and tumor uptake in a murine tumor model. In an initial biodistribution study with low molar activity, [68Ga]Ga-JB-1498 demonstrated salivary gland uptake of 0.13 ± 0.01%ID/g. In a second biodistribution study in non-tumor-bearing mice with high molar activity, [68Ga]Ga-JB1498 demonstrated salivary gland uptake of 0.39 ± 0.24% ID/g and kidney activity of 10.12 ± 1.73% ID/g at one hour post IV injection. This salivary gland uptake is significantly less than the published uptake of [68Ga]Ga-PSMA-11. Micro-PET visually confirmed the findings of the biodistribution studies. Dynamic micro-PET imaging demonstrated gradually decreasing [68Ga]Ga-JB1498 activity in salivary glands and kidneys, compared to gradually increasing [68Ga]Ga-PSMA-11 activity in these two organs during the first hour. CONCLUSION: Biodistribution and micro-PET imaging of [68Ga]Ga-JB-1498 demonstrate significantly decreased salivary gland uptake and different pharmacokinetic behavior in kidneys and salivary glands in mice compared to [68Ga]Ga-PSMA-11. Our findings suggest that constructing a PSMA-targeting molecule with a highly negatively charged linker is a promising strategy to reduce salivary gland uptake of GCP-II/PSMA ligands in theranostic applications.

CD6-targeted antibody-drug conjugate as a new therapeutic agent for T cell lymphoma.

T cell lymphomas (TCL) are heterogeneous, aggressive, and have few available targeted therapeutics. In this study, we determined that CD6, an established T cell marker, was expressed at high levels on almost all examined TCL patient specimens, suggesting that CD6 could be a new therapeutic target for this life-threatening blood cancer. We prepared a CD6-targeted antibody-drug conjugate (CD6-ADC) by conjugating monomethyl auristatin E (MMAE), an FDA-approved mitotic toxin, to a high-affinity anti-human CD6 monoclonal antibody (mAb). In contrast to both the unconjugated anti-CD6 mAb, and the non-binding control ADC, CD6-ADC potently and selectively killed TCL cells in vitro in both time- and concentration-dependent manners. It also prevented the development of tumors in vivo in a preclinical model of TCL. More importantly, systemic or local administration of the CD6-ADC or its humanized version, but not the controls, significantly shrank established tumors in the preclinical mouse model of TCL. These results suggest that CD6 is a novel therapeutic target in TCLs and provide a strong rationale for the further development of CD6-ADC as a promising therapy for patients with these potentially fatal lymphoid neoplasms.

18F-fluciclovine PET/CT to distinguish radiation necrosis from tumor progression for brain metastases treated with radiosurgery: results of a prospective pilot study.

PURPOSE: Distinguishing radiation necrosis from tumor progression among patients with brain metastases previously treated with stereotactic radiosurgery represents a common diagnostic challenge. We performed a prospective pilot study to determine whether PET/CT with 18F-fluciclovine, a widely available amino acid PET radiotracer, repurposed intracranially, can accurately diagnose equivocal lesions. METHODS: Adults with brain metastases previously treated with radiosurgery presenting with a follow-up tumor-protocol MRI brain equivocal for radiation necrosis versus tumor progression underwent an 18F-fluciclovine PET/CT of the brain within 30 days. The reference standard for final diagnosis consisted of clinical follow-up until multidisciplinary consensus or tissue confirmation. RESULTS: Of 16 patients imaged from 7/2019 to 11/2020, 15 subjects were evaluable with 20 lesions (radiation necrosis, n = 16; tumor progression, n = 4). Higher SUVmax statistically significantly predicted tumor progression (AUC = 0.875; p = 0.011). Lesion SUVmean (AUC = 0.875; p = 0.018), SUVpeak (AUC = 0.813; p = 0.007), and SUVpeak-to-normal-brain (AUC = 0.859; p = 0.002) also predicted tumor progression, whereas SUVmax-to-normal-brain (p = 0.1) and SUVmean-to-normal-brain (p = 0.5) did not. Qualitative visual scores were significant predictors for readers 1 (AUC = 0.750; p < 0.001) and 3 (AUC = 0.781; p = 0.045), but not for reader 2 (p = 0.3). Visual interpretations were significant predictors for reader 1 (AUC = 0.898; p = 0.012) but not for reader 2 (p = 0.3) or 3 (p = 0.2). CONCLUSIONS: In this prospective pilot study of patients with brain metastases previously treated with radiosurgery presenting with a contemporary MRI brain with a lesion equivocal for radiation necrosis versus tumor progression, 18F-fluciclovine PET/CT repurposed intracranially demonstrated encouraging diagnostic accuracy, supporting the pursuit of larger clinical trials which will be necessary to establish diagnostic criteria and performance.

Computational approaches to detect small lesions in 18 F-FDG PET/CT scans.

PURPOSE: When physicians interpret 18 F-FDG PET/CT scans, they rely on their subjective visual impression of the presence of small lesions, the criteria for which may vary among readers. Our investigation used physical phantom scans to evaluate whether image texture analysis metrics reliably correspond to visual criteria used to identify lesions and accurately differentiate background regions from sub-centimeter simulated lesions. METHODS: Routinely collected quality assurance test data were processed retrospectively for 65 different 18 F-FDG PET scans performed of standardized phantoms on eight different PET/CT systems. Phantoms included 8-, 12-, 16-, and 25-mm diameter cylinders embedded in a cylindrical water bath, prepared with 2.5:1 activity-to-background ratio emulating typical whole-body PET protocols. Voxel values in cylinder regions and background regions were sampled to compute several classes of image metrics. Two experienced physicists, blinded to quantified image metrics and to each other's readings, independently graded cylinder visibility on a 5-level scale (0 = definitely not visible to 4 = definitely visible). RESULTS: The three largest cylinders were visible in 100% of cases with a mean visibility score of 3.3 ± 1.2, while the smallest 8-mm cylinder was visible in 58% of cases with a significantly lower mean visibility score of 1.5±1.1 (P < 0.0001). By ROC analysis, the polynomial-fit signal-to-noise ratio was the most accurate at discriminating 8-mm cylinders from the background, with accuracy greater than visual detection (93% ± 2% versus 76% ± 4%, P = 0.0001), and better sensitivity (94% versus 58%, P < 0.0001). CONCLUSION: Image texture analysis metrics are more sensitive than visual impressions for detecting sub-centimeter simulated lesions. Therefore, image texture analysis metrics are potentially clinically useful for 18 F-FDG PET/CT studies.

Pilot Study of F18-Florbetapir in the Early Evaluation of Cardiac Amyloidosis.

Background: Cardiac amyloidosis is an increasingly recognized etiology of heart failure, in part due to the rise of non-invasive nuclear bone scintigraphy. Molecular imaging using positron emission tomography (PET) has promised the direct visualization of cardiac amyloid fibrils. We sought to assess the performance of F18-florbetapir PET in patients with a potential for cardiac amyloidosis in order to identify early disease. Methods: We performed a pilot study of 12 patients: one with asymptomatic transthyretin cardiac amyloidosis, seven with a potential for developing cardiac amyloidosis (two smoldering myeloma and five with extracardiac biopsy demonstrating transthyretin amyloid deposits and negative technetium pyrophosphate scans), and four controls. Patients were imaged with PET/CT in listmode 10-20 min after receiving F18-florbetapir. Static images were created from this acquisition, and mean standardized uptake values (SUVs) of the left ventricular myocardium, blood pool, paraspinal muscles, and liver were calculated. Results: All 12 patients demonstrated radiotracer uptake in the myocardium with mean SUV of 2.3 ± 0.4 and blood pool SUV of 0.8 ± 0.1. The patient with cardiac amyloidosis had SUV of 3.3, while mean SUV for patients at risk was 2.3 ± 0.4 and for controls was 2.2 ± 0.3. After 3 years of follow-up, one patient with SUV below the mean was subsequently diagnosed with ATTR cardiac amyloidosis. Conclusion: In this cohort, PET with F18-florbetapir demonstrated non-specific radiotracer uptake in the myocardium in all patients using a static image protocol; though, the highest values were noted in a patient with ATTR cardiac amyloidosis. There was no difference in the intensity of F18-florbetapir uptake in at-risk patients and controls. Future studies should continue to investigate metabolic PET tracers and protocols in cardiac amyloidosis, including in early disease.

Texture analysis for automated evaluation of Jaszczak phantom SPECT system tests.

PURPOSE: Routine quarterly quality assurance (QA) assessment of single photon emission computed tomography (SPECT) systems includes analysis of multipurpose phantoms containing spheres and rods of various sizes. When evaluated by accreditation agencies, criteria applied to assess image quality are largely subjective. Determining a quantified image characteristic metric that emulates human reader impressions of image quality could be quite useful. Our investigation was conducted to ascertain whether image texture analysis metrics, such as those applied to PET scans to detect neoplasms, could prove helpful in linking qualitative statements of phantom sphere and rod visibility to quantified parameters. Because it is not obvious whether it is preferable to submit reconstructions to accrediting agencies performed using typical clinical (CLIN) protocol processing parameters or to follow agencies' filtered backprojection (FBP) suggestions, we applied texture analysis metrics to determine the degree to which these choices affect equipment capability assessment. METHODS AND MATERIALS: Data were processed retrospectively for 125 different Tc-99 m SPECT scans of standardized phantoms for 14 rotating Anger detector systems as part of routine quarterly QA. Algorithms were written to compute several classes of image metrics: quantile curve metrics, image texture analysis gray-level co-occurrence matrix (GLCM) metrics, contrast metrics, and count histogram metrics. For qualitative image scores, two experienced physicists independently graded sphere and rod visibility on a 5-level scale and assigned dichotomous visibility scores, without knowledge of quantified texture analysis metrics or each other's readings. The same phantom was used to collect 15 additional data sets with two dual-detector SPECT/CT systems, reconstructed both by FBP parameters that have been suggested by accrediting agencies and by manufacturers' default settings for CLIN SPECT/CT bone imaging protocols by ordered subsets expectation maximization (OSEM), incorporating attenuation correction using the CT scan. Image characteristics metrics were compared for FBP and CLIN reconstructions. RESULTS: For spheres, the metric with the strongest rank correlation with 5-level scale readings was the quantile curve slope (ρ = 0.83, P < 0.0001), while for rods it was GLCM Energy normalized to the maximum GLCM Energy value (EnergyNorm) (ρ = -0.88, P < 0.0001). Compared to dichotomous readings, the metric with the highest ROC area under curve (AUC) for spheres was the quantile curve slopes (AUC = 96 ± 1%, sensitivity = 91%, specificity = 90%), and for rods was EnergyNorm (AUC = 98 ± 1%, sensitivity = 92%, specificity = 95%). Image contrast was higher for all sphere sizes and rod EnergyNorm was lower for sectors of intermediate-sized rods for FBP compared to CLIN reconstructions, in agreement with more rods judged to be visible from FBP than CLIN reconstructions (47% vs 33%, P = 0.002). CONCLUSIONS: When preparing to submit quality assurance images of standardized phantoms to accrediting agencies, a reliable gauge of sphere and rod visibility can be predicted accurately using quantified reader-independent image texture analysis metrics, which also provide a useful basis for choosing among alternative image reconstruction options.

Loss of dihydrotestosterone-inactivation activity promotes prostate cancer castration resistance detectable by functional imaging.

Androgens such as testosterone and dihydrotestosterone are a critical driver of prostate cancer progression. Cancer resistance to androgen deprivation therapies ensues when tumors engage metabolic processes that produce sustained androgen levels in the tissue. However, the molecular mechanisms involved in this resistance process are unclear, and functional imaging modalities that predict impending resistance are lacking. Here, using the human LNCaP and C4-2 cell line models of prostate cancer, we show that castration treatment-sensitive prostate cancer cells that normally have an intact glucuronidation pathway that rapidly conjugates and inactivates dihydrotestosterone and thereby limits androgen signaling, become glucuronidation deficient and resistant to androgen deprivation. Mechanistically, using CRISPR/Cas9-mediated gene ablation, we found that loss of UDP glucuronosyltransferase family 2 member B15 (UGT2B15) and UGT2B17 is sufficient to restore free dihydrotestosterone, sustained androgen signaling, and development of castration resistance. Furthermore, loss of glucuronidation enzymatic activity was also detectable with a nonsteroid glucuronidation substrate. Of note, glucuronidation-incompetent cells and the resultant loss of intracellular conjugated dihydrotestosterone were detectable in vivo by 18F-dihydrotestosterone PET. Together, these findings couple a mechanism with a functional imaging modality to identify impending castration resistance in prostate cancers.

Multi institutional quantitative phantom study of yttrium-90 PET in PET/MRI: the MR-QUEST study.

BACKGROUND: Yttrium-90 (90Y) radioembolization involves the intra-arterial delivery of radioactive microspheres to treat hepatic malignancies. Though this therapy involves careful pre-treatment planning and imaging, little is known about the precise location of the microspheres once they are administered. Recently, there has been growing interest post-radioembolization imaging using positron-emission tomography (PET) for quantitative dosimetry and identifying lesions that may benefit from additional salvage therapy. In this study, we aim to measure the inter-center variability of 90Y PET measurements as measured on PET/MRI in preparation for a multi-institutional prospective phase I/II clinical trial. Eight institutions participated in this study and followed a standardized phantom filling and imaging protocol. The NEMA NU2-2012 body phantom was filled with 3 GBq of 90Y chloride solution. The phantom was imaged for 30 min in listmode on a Siemens Biograph mMR non-TOF PET/MRI scanner at five time points across 10 days (0.3-3.0 GBq). Raw PET data were sent to a central site for image reconstruction and data analysis. Images were reconstructed with optimal parameters determined from a previous study. Volumes of interest (VOIs) matching the known sphere diameters were drawn on the vendor-provided attenuation map and propagated to the PET images. Recovery coefficients (RCs) and coefficient of variation of the RCs (COV) were calculated from these VOIs for each sphere size and activity level. RESULTS: Mean RCs ranged from 14.5 to 75.4%, with the lowest mean RC coming from the smallest sphere (10 mm) on the last day of imaging (0.16 MBq/ml) and the highest mean RC coming from the largest sphere (37 mm) on the first day of imaging (2.16 MBq/ml). The smaller spheres tended to exhibit higher COVs. In contrast, the larger spheres tended to exhibit lower COVs. COVs from the 37 mm sphere were < 25.3% in all scans. For scans with ≥ 0.60 MBq/ml, COVs were ≤ 25% in spheres ≥ 22 mm. However, for all other spheres sizes and activity levels, COVs were usually > 25%. CONCLUSIONS: Post-radioembolization dosimetry of lesions or other VOIs ≥ 22 mm in diameter can be consistently obtained (< 25% variability) at a multi-institutional level using PET/MRI for any clinically significant activity for 90Y radioembolization.

Impact of Time-of-Flight Reconstruction on Cardiac PET Images of Obese Patients.

PURPOSE: The benefit of time-of-flight (TOF) information in PET oncology studies is well established, demonstrating improved signal-to-noise ratio and enhanced lesion detection. In cardiac PET studies, tracer distribution and study interpretation differ substantially from oncology PET, and the benefit of TOF is less established. We investigate the impact of TOF on reconstructed myocardial distribution in Rb PET perfusion studies of obese patients, for whom TOF would have most significant impact. METHODS: Cardiac Rb PET data of 13 obese patients (8 male, 5 female patients; weight, mean, 139 kg [range, 109-191 kg]; body mass index, mean, 49 kg/m [range, 36-76 kg/m]) were analyzed retrospectively. Images were reconstructed with and without TOF and with varying number of iterative updates (2-12 iterations). Convergence and clinical relevance of differences were assessed both visually and quantitatively (automated 17-segment scoring). An anthropomorphic torso phantom also was scanned in order to study how TOF affects reconstruction of a myocardial distribution. RESULTS: Time-of-flight imaging provided significant improvement in image quality and convergence rate compared with non-TOF imaging. Time-of-flight reconstruction typically required 2 to 4 iterations to converge versus 8 to 12 iterations for non-TOF reconstruction. Even at 12 iterations, non-TOF images occasionally had apparent differences in relative perfusion compared with TOF images that exceeded 10% and were considered likely to affect clinical interpretation. CONCLUSIONS: Time-of-flight reconstruction has a significant clinical impact on cardiac PET in obese patients. When interpreting cardiac studies from non-TOF-capable PET scanners, one must ensure to reconstruct images with sufficient iterations and to be aware of potential artifacts.

Do myocardial PET-MR and PET-CT FDG images provide comparable information?

INTRODUCTION: Although positron emission tomography PET-MR imaging is emerging into clinical practice, many aspects of this imaging technique such as attenuation correction have yet to be validated for myocardial imaging. Thus, it is uncertain whether PET-MR FDG images provide clinical information which is comparable to PET-CT FDG images. The study goal was to systematically compare relative myocardial FDG concentrations obtained from cardiac PET-MR images to those derived from same day PET-CT images. METHODS: Myocardial FDG images of 27 patients undergoing PET-CT imaging, followed by PET-MR imaging 42 ± 13 minutes later as part of a prospective oncology study were analyzed. Mean segmental standardized uptake measurements (SUVmean) were obtained in each of the 17 standard myocardial segments and normalized to the brightest segment. RESULTS: Normalized segmental SUVmean values did not differ significantly between the PET-MR and PET-CT images (mean difference 0.002, P = .826). The specific segment was a marginally significant predictor of the differences (P = .057), with the largest difference in the anteroseptal basal segment. CONCLUSIONS: PET-MR, vis-à-vis PET-CT, does not significantly raise segmental uptake relative to the brightest segment, suggesting that PET-MR can be used similarly to PET-CT for applications where relative uptake is important.

Transmission Imaging in Lymphoscintigraphy with a 153Gd Flood Source.

UNLABELLED: Lymphoscintigraphy uses intradermal or interstitial injections of (99m)Tc-labeled tracers to produce images of focal lymph nodes. Because there is little or no anatomic information in the (99m)Tc images, a (57)Co flood source is sometimes used to provide transmission data along with the emission data. The anatomic shadow from the transmission scan generally improves interpretation and surgical planning. However, the (57)Co transmission photons contribute to background on the (99m)Tc images, reducing contrast and signal-to-noise ratio (SNR). SNR is related to lesion detection, and some lymph nodes that would be detected in an emission-only scan might not be detected if acquired with a (57)Co flood source. An alternative to a (57)Co flood source is a (153)Gd flood source, which has primary photon emissions well below the (99m)Tc emission window, allowing the shadow to be acquired in a separate transmission window. Significantly smaller crosstalk from (153)Gd should improve SNR and therefore would be expected to improve lymph node detection. We hypothesized that the use of a (153)Gd flood source would reduce background and improve SNR for these studies. METHODS: Phantom studies simulating lymphoscintigraphy were performed to compare performance with a (153)Gd flood source, a (57)Co flood source, and no flood source. SNR in the (99m)Tc emission images was measured using a water phantom to simulate patient body and point sources of various activities to simulate nodes and injection site. The encouraging phantom studies prompted use of the (153)Gd flood source in routine clinical breast lymphoscintigraphy, melanoma lymphoscintigraphy, and lymphedema studies. Because emission and transmission data were acquired in separate energy windows, fused planar images of emission and transmission data were available to the physician. RESULTS: SNR was highest with no flood source and was lowest with the (57)Co flood source by a significant margin. SNR with the (153)Gd flood source was similar to that with no flood source on the anterior (transmission) view. SNR was reduced somewhat in the posterior (nontransmission) view because of attenuation of signal by the flood source itself. Minor crosstalk in the (99m)Tc window was observed with the (153)Gd flood source, attributed to simultaneous detection of x-ray photons and gamma-photons. This crosstalk was reduced by introducing thin metal filters to absorb most x-ray photons, at the expense of more attenuation in the posterior view. Unlike with the (57)Co flood source, a usable posterior view (with anatomic shadow derived from the anterior view) was generated with the (153)Gd flood source. Clinical lymphoscintigraphy images with the (153)Gd flood source were of high quality. Interpretation was aided by the ability to control image mixing and brightness and contrast of separate color scales. CONCLUSION: By producing fused images with reduced crosstalk and improved image quality, a (153)Gd flood source offers advantages over a conventional (57)Co flood source for anatomic shadowing in lymphoscintigraphy. Lymph nodes in emission images have higher SNR, indicating a likely improvement in clinical lesion detection. Separate emission and transmission images provide additional flexibility in image display during interpretation.

Determination of Radiation Absorbed Dose to Primary Liver Tumors and Normal Liver Tissue Using Post-Radioembolization (90)Y PET.

BACKGROUND: Radioembolization with Yttrium-90 ((90) Y) microspheres is becoming a more widely used transcatheter treatment for unresectable hepatocellular carcinoma (HCC). Using post-treatment (90) Y positron emission tomography/computerized tomography (PET/CT) scans, the distribution of microspheres within the liver can be determined and quantitatively assessed. We studied the radiation dose of (90) Y delivered to liver and treated tumors. METHODS: This retrospective study of 56 patients with HCC, including analysis of 98 liver tumors, measured and correlated the dose of radiation delivered to liver tumors and normal liver tissue using glass microspheres (TheraSpheres(®)) to the frequency of complications with modified response evaluation criteria in solid tumors (mRECIST). (90) Y PET/CT and triphasic liver CT scans were used to contour treated tumor and normal liver regions and determine their respective activity concentrations. An absorbed dose factor was used to convert the measured activity concentration (Bq/mL) to an absorbed dose (Gy). RESULTS: The 98 studied tumors received a mean dose of 169 Gy (mode 90-120 Gy; range 0-570 Gy). Tumor response by mRECIST criteria was performed for 48 tumors that had follow-up scans. There were 21 responders (mean dose 215 Gy) and 27 non-responders (mean dose 167 Gy). The association between mean tumor absorbed dose and response suggests a trend but did not reach statistical significance (p = 0.099). Normal liver tissue received a mean dose of 67 Gy (mode 60-70 Gy; range 10-120 Gy). There was a statistically significant association between absorbed dose to normal liver and the presence of two or more severe complications (p = 0.036). CONCLUSION: Our cohort of patients showed a possible dose-response trend for the tumors. Collateral dose to normal liver is non-trivial and can have clinical implications. These methods help us understand whether patient adverse events, treatment success, or treatment failure can be attributed to the dose that the tumor or normal liver received.

Improving the biodistribution of PSMA-targeting tracers with a highly negatively charged linker.

BACKGROUND: Prostate specific membrane antigen (PSMA) is overexpressed in prostate cancer and in tumor vasculature. Small molecule based inhibitors of PSMA have promised to provide sensitive detection of primary and metastatic prostate tumors. Although significant progress has been made, many of the radiolabeled imaging agents exhibit non-specific background binding. Prevailing tracer designs focus on high affinity urea-based inhibitors with strategically placed hydrophobic patches that interact favorably with the substrate tunnel of PSMA. We hypothesized that a novel PSMA inhibitor design incorporating highly negatively charged linkers may minimize non-specific binding and decrease overall background. METHODS: Through iterative redesign, we generated a series of PSMA inhibitors with highly negatively charged linkers that connect to urea inhibitors and bulky radionuclide chelates. We then performed in vivo imaging and biodistribution studies with the radiolabeled tracers. RESULTS: The tracers derived from our iterative redesign have affinities for PSMA comparable to the "parent" urea ligand Cys-C(O)-Glu. Using a fluorine-18 labeled PSMA targeting tracer, we found that these highly negatively charged molecules exhibit rapid renal excretion with minimal non-specific binding. The biodistribution data at 2 hr showed 4.6%ID/g PC3-PIP tumor uptake with spleen, liver, bone, and blood background levels of 0.1%, 0.17%, 0.1%, and 0.04%, respectively. CONCLUSION: Placement of multiple negative charges in the linker region of PSMA tracers significantly reduced the non-specific background binding without significant reduction of binding affinity. This increased tumor/background contrast in positron emission tomography promises to provide more sensitive tumor detection while decreasing the overall radiation exposure to patients.

Fasting 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography to detect metabolic changes in pulmonary arterial hypertension hearts over 1 year.

BACKGROUND: The development of tools to monitor the right ventricle in pulmonary arterial hypertension (PAH) is of clinical importance. PAH is associated with pathologic expression of the transcription factor hypoxia-inducible factor (HIF)-1α, which induces glycolytic metabolism and mobilization of proangiogenic progenitor (CD34(+)CD133(+)) cells. We hypothesized that PAH cardiac myocytes have a HIF-related switch to glycolytic metabolism that can be detected with fasting 2-deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography (FDG-PET) and that glucose uptake is informative for cardiac function. METHODS: Six healthy control subjects and 14 patients with PAH underwent fasting FDG-PET and echocardiogram. Blood CD34(+)CD133(+) cells and erythropoietin were measured as indicators of HIF activation. Twelve subjects in the PAH cohort underwent repeat studies 1 year later to determine if changes in FDG uptake were related to changes in echocardiographic parameters or to measures of HIF activation. MEASUREMENTS AND RESULTS: FDG uptake in the right ventricle was higher in patients with PAH than in healthy control subjects and correlated with echocardiographic measures of cardiac dysfunction and circulating CD34(+)CD133(+) cells but not erythropoietin. Among patients with PAH, FDG uptake was lower in those receiving ß-adrenergic receptor blockers. Changes in FDG uptake over time were related to changes in echocardiographic parameters and CD34(+)CD133(+) cell numbers. Immunohistochemistry of explanted PAH hearts of patients undergoing transplantation revealed that HIF-1α was present in myocyte nuclei but was weakly detectable in control hearts. CONCLUSIONS: PAH hearts have pathologic glycolytic metabolism that is quantitatively related to cardiac dysfunction over time, suggesting that metabolic imaging may be useful in therapeutic monitoring of patients.

Lung dose calculation with SPECT/CT for 9°Yittrium radioembolization of liver cancer.

PURPOSE: To propose a new method to estimate lung mean dose (LMD) using technetium-99m labeled macroaggregated albumin ((99m)Tc-MAA) single photon emission CT (SPECT)/CT for (90)Yttrium radioembolization of liver tumors and to compare the LMD estimated using SPECT/CT with clinical estimates of LMD using planar gamma scintigraphy (PS). METHODS AND MATERIALS: Images of 71 patients who had SPECT/CT and PS images of (99m)Tc-MAA acquired before TheraSphere radioembolization of liver cancer were analyzed retrospectively. LMD was calculated from the PS-based lung shunt assuming a lung mass of 1 kg and 50 Gy per GBq of injected activity shunted to the lung. For the SPECT/CT-based estimate, the LMD was calculated with the activity concentration and lung volume derived from SPECT/CT. The effect of attenuation correction and the patient's breathing on the calculated LMD was studied with the SPECT/CT. With these effects correctly taken into account in a more rigorous fashion, we compared the LMD calculated with SPECT/CT with the LMD calculated with PS. RESULTS: The mean dose to the central region of the lung leads to a more accurate estimate of LMD. Inclusion of the lung region around the diaphragm in the calculation leads to an overestimate of LMD due to the misregistration of the liver activity to the lung from the patient's breathing. LMD calculated based on PS is a poor predictor of the actual LMD. For the subpopulation with large lung shunt, the mean overestimation from the PS method for the lung shunt was 170%. CONCLUSIONS: A new method of calculating the LMD for TheraSphere and SIR-Spheres radioembolization of liver cancer based on (99m)Tc-MAA SPECT/CT is presented. The new method provides a more accurate estimate of radiation risk to the lungs. For patients with a large lung shunt calculated from PS, a recalculation of LMD based on SPECT/CT is recommended.