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1.  Influence of Bioluminescence Imaging Dynamics by D-Luciferin Uptake and Efflux Mechanisms 
Molecular imaging  2012;11(6):499-506.
Bioluminescence imaging (BLI) detects light generated by luciferase-mediated oxidation of substrate and is used widely for evaluating transgene expression in cell-based assays and in vivo in relevant preclinical models. The most commonly used luciferase for in vivo applications is firefly luciferase (fLuc), for which D-luciferin serves as the substrate. We demonstrated previously that the expression of the ABCG2 efflux transporter can significantly reduce BLI signal output and that HhAntag-691 can inhibit the efflux of D-luciferin, thereby enhancing BLI signal. Here we show that an HhAntag-691-sensitive uptake mechanism facilitates the intracellular concentration of D-luciferin and that the BLI dynamics of different cell lines are coregulated by this uptake mechanism in conjunction with ABCG2-mediated efflux. After administration of D-luciferin, the HhAntag-691-sensitive uptake mechanism generates a rapid increase in BLI signal that decreases over time, whereas ABCG2-mediated efflux stably reduces signal output. We implicate SLC22A4 (OCTN1), a member of the organic cation/zwitterion uptake transporter family, as one potential mediator of the HhAntag-691-sensitive D-luciferin uptake. These findings provide insight into mechanisms that contribute to the cellular uptake kinetics and in vivo biodistribution of D-luciferin.
PMCID: PMC4332814  PMID: 23084250
2.  The Evolution of Imaging in Cancer: Current State and Future Challenges 
Seminars in oncology  2011;38(1):3-15.
Molecular imaging allows for the remote, noninvasive sensing and measurement of cellular and molecular processes in living subjects. Drawing upon a variety of modalities, molecular imaging provides a window into the biology of cancer from the subcellular level to the patient undergoing a new, experimental therapy. As signal transduction cascades and protein interaction networks become clarified, an increasing number of relevant targets for cancer therapy—and imaging—become available. Although conventional imaging is already critical to the management of patients with cancer, molecular imaging will provide even more relevant information, such as early detection of changes with therapy, identification of patient-specific cellular and metabolic abnormalities, and the disposition of therapeutic, gene-tagged cells throughout the body—all of which will have a considerable impact on morbidity and mortality. This overview discusses molecular imaging in oncology, providing examples from a variety of modalities, with an emphasis on emerging techniques for translational imaging.
PMCID: PMC4313866  PMID: 21362512
3.  AEG-1 promoter-mediated imaging of prostate cancer 
Cancer research  2014;74(20):5772-5781.
We describe a new imaging method for detecting prostate cancer, whether localized or disseminated and metastatic to soft tissues and bone. The method relies on the use of imaging reporter genes under the control of the promoter of AEG-1 (MTDH), which is selectively active only in malignant cells. Through systemic, nanoparticle-based delivery of the imaging construct, lesions can be identified through bioluminescence imaging and single photon emission-computed tomography in the PC3-ML murine model of prostate cancer at high sensitivity. This approach is applicable for the detection of prostate cancer metastases, including bone lesions for which there is no current reliable agent for non-invasive clinical imaging. Further, the approach compares favorably to accepted and emerging clinical standards, including positron emission tomography with [18F]fluorodeoxyglucose and [18F]sodium fluoride. Our results offer a preclinical proof of concept that rationalizes clinical evaluation in patients with advanced prostate cancer.
PMCID: PMC4234089  PMID: 25145668
molecular-genetic imaging; bioluminescence; SPECT; metastasis; nanoparticle; PC3
4.  A red-shifted fluorescent substrate for aldehyde dehydrogenase 
Nature communications  2014;5:3662.
Selection of cells positive for aldehyde dehydrogenase (ALDH) activity from a green fluorescent background is difficult with existing reagents. Here we report a red-shifted fluorescent substrate for ALDH, AldeRed 588-A, for labeling viable ALDHpos cells. We demonstrate that AldeRed 588-A successfully isolates ALDHhi human hematopoietic stem cells from heterogeneous cord blood mononuclear cells. AldeRed 588-A can be used for multi-color applications to fractionate ALDHpos cells in the presence of green fluorophores including the ALDEFLUOR™ reagent and cells expressing eGFP. AldeRed 588-A stains ALDHpos murine pancreatic centroacinar and terminal duct cells, as visualized by fluorescent microscopy. AldeRed588-A provides a useful tool to select stem cells or study ALDH within a green fluorescent background.
PMCID: PMC4063304  PMID: 24759454
5.  Translational Molecular Imaging of Prostate Cancer 
Current radiology reports  2013;1(3):216-226.
Prostate cancer is a heterogeneous disease, and its management is now evolving to become more personalized and to incorporate new targeted therapies. With these new changes comes a demand for molecular imaging techniques that can not only detect disease but also assess biology and treatment response. This review article summarizes current molecular imaging approaches in prostate cancer (e.g. 99mTc bone scintigraphy and 18F-fluorodeoxyglucose positron emission tomography) and highlights emerging clinical and preclinical imaging agents, with an emphasis on mechanism and clinical application. Emerging agents at various stages of clinical translation include radiolabeled analogs of lipid, amino acid, and nucleoside metabolism, as well as agents more specifically targeting prostate cancer biomarkers including androgen receptor, prostate-specific membrane antigen and others. We also highlight new techniques and targeted contrast agents for magnetic resonance imaging and spectroscopy. For all these imaging techniques, a growing and important unmet need is for well-designed prospective clinical trials to establish clear indications with clinical benefit in prostate cancer.
PMCID: PMC3804343  PMID: 24159427
Molecular imaging; prostate cancer; positron emission tomography; magnetic resonance imaging; single photon emission computed tomography; prostate-specific membrane antigen; androgen receptor
6.  Effect of Chelators on the Pharmacokinetics of 99mTc-Labeled Imaging Agents for the Prostate-Specific Membrane Antigen (PSMA) 
Journal of medicinal chemistry  2013;56(15):6108-6121.
Technetium-99m, the most commonly used radionuclide in nuclear medicine, can be attached to biologically important molecules through a variety of chelating agents, the choice of which depends upon the imaging application. The prostate-specific membrane antigen (PSMA) is increasingly recognized as an important target for imaging and therapy of prostate cancer (PCa). Three different 99mTc-labeling methods were employed to investigate the effect of the chelator on the biodistribution and PCa tumor uptake profiles of 12 new urea based PSMA-targeted radiotracers. This series includes hydrophilic ligands for radiolabeling with the [99mTc(CO)3]+ core (L8-10), traditional NxSy-based chelating agents with varying charge and polarity for the 99mTc-oxo core (L11-18), and a 99mTc-organohydrazine-labeled radioligand (L19). 99mTc(I)-Tricarbonyl-labeled [99mTc]L8 produced the highest PSMA+ PC3 PIP to PSMA− PC3 flu tumor ratios, and demonstrated the lowest retention in normal tissues including kidney after 2 h. These results suggest that choice of chelator is an important pharmacokinetic consideration in the development of 99mTc-labeled radiopharmaceuticals targeting PSMA.
PMCID: PMC3773988  PMID: 23799782
7.  Evaluation of Prostate-Specific Membrane Antigen as an Imaging Reporter 
Genetic reporters provide a noninvasive method to monitor and evaluate a population of cells. The ideal properties of a gene reporter-probe system include biocompatibility, lack of immunogenicity, low background expression or signal, and high sensitivity of detection. The prostate-specific membrane antigen (PSMA) is an attractive candidate for a genetic reporter as it is a human trans-membrane protein with a selective expression pattern, and there are several PSMA imaging agents available for clinical and preclinical applications. We evaluated the use of PSMA as a genetic imaging reporter by comparison to 2 clinically established reporters, the mutant herpes simplex virus type I thymidine kinase and the human sodium-iodide symporter.
Adenoviruses expressing each reporter were constructed and validated in vitro for expression and function. To compare PSMA with existing imaging reporters, a bilateral Matrigel suspension model was established with nude mice bearing cells equally infected with each reporter or control adenovirus. Dynamic PET was performed, and time–activity curves were generated for each reporter-probe pair.
A comparison of peak target-to-background ratios revealed that PSMA offered the highest ratio relative to the control Matrigel suspension as well as muscle. Further, as proof of concept, PSMA was applied as an imaging reporter to monitor adenoviral liver transduction with both nuclear and optical imaging probes.
These preliminary studies support further development of PSMA as a noninvasive genetic reporter.
PMCID: PMC4074907  PMID: 24700883
PSMA; molecular-genetic imaging; DCFPyL; positron emission tomography; optical imaging
8.  Clinical Applications of Gallium-68 
Gallium-68 is a positron-emitting radioisotope that is produced from a 68Ge/68Ga generator. As such it is conveniently used, decoupling radiopharmacies from the need for a cyclotron on site. Gallium-68-labeled peptides have been recognized as a new class of radiopharmaceuticals showing fast target localization and blood clearance. 68Ga-DOTATOC, 8Ga-DOTATATE, 68Ga-DOTANOC, are the most prominent radiopharmaceuticals currently in use for imaging and differentiating lesions of various somatostatin receptor subtypes, overexpressed in many neuroendocrine tumors. There has been a tremendous increase in the number of clinical studies with 68Ga over the past few years around the world, including within the United States. An estimated ~10,000 scans are being performed yearly in Europe at about 100 centers utilizing 68Ga-labeled somatostatin analogs within clinical trials. Two academic sites within the US have also begun to undertake human studies. This review will focus on the clinical experience of selected, well-established and recently applied 68Ga-labeled imaging agents used in nuclear medicine.
PMCID: PMC3664132  PMID: 23522791
PET; radiopeptides; somatostatin receptor; neuroendocrine tumor; clinical trials
9.  Molecular Imaging of Conscious, Unrestrained Mice with AwakeSPECT 
We have developed a SPECT imaging system, AwakeSPECT, to enable molecular brain imaging of untrained mice that are conscious, unanesthetized, and unrestrained. We accomplished this with head tracking and motion correction techniques.
The capability of the system for motion-corrected imaging was demonstrated with a 99mTc-pertechnetate phantom, 99mTcmethylene diphosphonate bone imaging, and measurement of the binding potential of the dopamine transporter radioligand 123I-ioflupane in mouse brain in the awake and anesthetized (isoflurane) states. Stress induced by imaging in the awake state was assessed through measurement of plasma corticosterone levels.
AwakeSPECT provided high-resolution bone images reminiscent of those obtained from CT. The binding potential of 123I-ioflupane in the awake state was on the order of 50% of that obtained with the animal under anesthesia, consistent with previous studies in nonhuman primates. Levels of stress induced were on the order of those seen in other behavioral tasks and imaging studies of awake animals.
These results demonstrate the feasibility of SPECT molecular brain imaging of mice in the conscious, unrestrained state and demonstrate the effects of isoflurane anesthesia on radiotracer uptake.
PMCID: PMC3965297  PMID: 23536223
awake; mouse; SPECT; anesthesia; ioflupane
10.  64Cu-Labeled Inhibitors of Prostate-Specific Membrane Antigen for PET Imaging of Prostate Cancer 
Journal of Medicinal Chemistry  2014;57(6):2657-2669.
Prostate-specific membrane antigen (PSMA) is a well-recognized target for identification and therapy of a variety of cancers. Here we report five 64Cu-labeled inhibitors of PSMA, [64Cu]3–7, which are based on the lysine–glutamate urea scaffold and utilize a variety of macrocyclic chelators, namely NOTA(3), PCTA(4), Oxo-DO3A(5), CB-TE2A(6), and DOTA(7), in an effort to determine which provides the most suitable pharmacokinetics for in vivo PET imaging. [64Cu]3–7 were prepared in high radiochemical yield (60–90%) and purity (>95%). Positron emission tomography (PET) imaging studies of [64Cu]3–7 revealed specific accumulation in PSMA-expressing xenografts (PSMA+ PC3 PIP) relative to isogenic control tumor (PSMA– PC3 flu) and background tissue. The favorable kinetics and high image contrast provided by CB-TE2A chelated [64Cu]6 suggest it as the most promising among the candidates tested. That could be due to the higher stability of [64Cu]CB-TE2A as compared with [64Cu]NOTA, [64Cu]PCTA, [64Cu]Oxo-DO3A, and [64Cu]DOTA chelates in vivo.
PMCID: PMC3983358  PMID: 24533799
11.  Biodistribution, Tumor Detection, and Radiation Dosimetry of 18F-DCFBC, a Low-Molecular-Weight Inhibitor of Prostate-Specific Membrane Antigen, in Patients with Metastatic Prostate Cancer 
Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-Lcysteine (18F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of 18F-DCFBC in men with metastatic PCa.
Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of 18F-DCFBC. Serial PET was performed until 2 h after administration. Time- activity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1.
Most vascular organs demonstrated a slow decrease in radioactivity concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (µGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 ± 1.34 µSv/MBq (mean ± SD).
Although further studies are needed for validation, our findings demonstrate the potential of 18F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for 18F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as 18F-FDG.
PMCID: PMC3742115  PMID: 23203246
prostate-specific membrane antigen; prostate cancer; 18F; urea; PET/CT
12.  Experimental Evaluation of Depth-of-Interaction Correction in a Small-Animal Positron Emission Tomography Scanner 
Molecular imaging  2010;9(6):311-318.
Human and small-animal positron emission tomography (PET) scanners with cylindrical geometry and conventional detectors exhibit a progressive reduction in radial spatial resolution with increasing radial distance from the geometric axis of the scanner. This “depth-of-interaction” (DOI) effect is sufficiently deleterious that many laboratories have devised novel schemes to reduce the magnitude of this effect and thereby yield PET images of greater quantitative accuracy. Here we examine experimentally the effects of a particular DOI correction method (dual-scintillator phoswich detectors with pulse shape discrimination) implemented in a small-animal PET scanner by comparing the same phantom and same mouse images with and without DOI correction. The results suggest that even this relatively coarse, two-level estimate of radial gamma ray interaction position significantly reduces the DOI parallax error. This study also confirms two less appreciated advantages of DOI correction: a reduction in radial distortion and radial source displacement as a source is moved toward the edge of the field of view and a resolution improvement detectable in the central field of view likely owing to improved spatial sampling.
PMCID: PMC3700348  PMID: 21084028
13.  Heterobivalent Agents Targeting PSMA and Integrin-αvβ3 
Bioconjugate Chemistry  2014;25(2):393-405.
Differential expression of surface proteins on normal vs malignant cells provides the rationale for the development of receptor-, antigen-, and transporter-based, cancer-selective imaging and therapeutic agents. However, tumors are heterogeneous, and do not always express what can be considered reliable, tumor-selective markers. That suggests development of more flexible targeting platforms that incorporate multiple moieties enabling concurrent targeting to a variety of putative markers. We report the synthesis, biochemical, in vitro, and preliminary in vivo evaluation of a new heterobivalent (HtBv) imaging agent targeting both the prostate-specific membrane antigen (PSMA) and integrin-αvβ3 surface markers, each of which can be overexpressed in certain tumor epithelium and/or neovasculature. The HtBv agent was functionalized with either 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or the commercially available IRDye800CW. DOTA-conjugated HtBv probe 9 bound to PSMA or αvβ3 with affinities similar to those of monovalent (Mnv) compounds designed to bind to their targets independently. In situ energy minimization experiments support a model describing the conformations adapted by 9 that enable it to bind both targets. IRDye800-conjugated HtBv probe 10 demonstrated target-specific binding to either PSMA or integrin-αvβ3 overexpressing xenografts. HtBv agents 9 and 10 may enable dual-targeted imaging of malignant cells and tissues in an effort to address heterogeneity that confounds many cancer-targeted imaging agents.
PMCID: PMC4112557  PMID: 24410012
14.  Noninvasive Molecular Imaging of Tuberculosis-Associated Inflammation With Radioiodinated DPA-713 
The Journal of Infectious Diseases  2013;208(12):2067-2074.
Background. Increased expression of translocator protein (TSPO) is a feature of microglial and macrophage activation. Since activated macrophages are key components of tuberculosis-associated inflammation, we evaluated radioiodinated DPA-713, a synthetic ligand of TSPO, for in vivo imaging of host response.
Methods. Mice were infected with aerosolized Mycobacterium tuberculosis and evaluated using whole-body [125I]iodo-DPA-713 single-photon emission computed tomography (SPECT). Ex vivo biodistribution and correlative immunofluorescence studies were also performed.
Results. [125I]Iodo-DPA-713 SPECT imaging clearly delineated tuberculosis-associated pulmonary inflammation in live animals. Biodistribution studies confirmed radiotracer specificity for inflamed pulmonary tissues. Immunofluorescence studies demonstrated that TSPO is highly expressed in CD68+ macrophages and phagocytic cells within tuberculosis lesions and that [125I]DPA-713 specifically accumulates within these cells. Coadministration of excess unlabelled DPA-713 abrogated both the SPECT and ex vivo fluorescence signals. Lesion-specific signal-to-noise ratios were significantly higher with [125I]iodo-DPA-713 SPECT (4.06 ± 0.52) versus [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) (2.00 ± 0.28) performed in the same mice (P = .004).
Conclusions. [125I]Iodo-DPA-713 accumulates specifically in tuberculosis-associated inflammatory lesions by selective retention within macrophages and phagocytic cells. [125I]Iodo-DPA-713 SPECT provides higher lesion-specific signal-to-noise ratios than [18F]FDG PET and may prove to be a more specific biomarker to monitor tuberculosis in situ.
PMCID: PMC3836460  PMID: 23901092
translocator protein; molecular imaging; tuberculosis; PET; pyrazolopyrimidine; macrophage
15.  2-(3-{1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, [18F]DCFPyL, a PSMA-based PET Imaging Agent for Prostate Cancer 
We have synthesized and evaluated in vivo 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, [18F]DCFPyL, as a potential imaging agent for the prostate-specific membrane antigen, PSMA. PSMA is upregulated in prostate cancer epithelia as well as in the neovasculature of most solid tumors.
Experimental Design
[18F]DCFPyL was synthesized in two steps from the p-methoxybenzyl (PMB) protected lys-C(O)-glu urea precursor using 6-[18F]fluoronicotinic acid tetrafluorophenyl ester ([18F]F-Py-TFP) for introduction of 18F. Radiochemical synthesis was followed by biodistribution and imaging with PET in immunocompromised mice using isogenic PC3 PSMA+ and PSMA− xenograft models. Human radiation dosimetry estimates were calculated using OLINDA/EXM 1.0.
DCFPyL displays a Ki value of 1.1 ± 0.1 nM for PSMA. [18F]DCFPyL was produced in radiochemical yields of 36-53% (decay corrected) and specific radioactivities of 340 – 480 Ci/mmol (12.6 – 17.8 GBq/μmol, n = 3). In an immunocompromised mouse model [18F]DCFPyL clearly delineated PSMA+ PC3 PIP prostate tumor xenografts on imaging with PET. At 2 h post-injection, 39.4 ± 5.4 percent injected dose per gram of tissue (%ID/g) was evident within the PIP tumor, with a ratio of 358:1 of uptake within PIP to PSMA− PC3 flu tumor placed in the opposite flank. At or after 1 h post-injection, minimal non-target tissue uptake of [18F]DCFPyL was observed. The bladder wall is the dose-limiting organ.
These data suggest [18F]DCFPyL as a viable, new positron-emitting imaging agent for PSMA-expressing tissues.
PMCID: PMC3243762  PMID: 22042970
PSMA; PET; molecular imaging; prostate cancer; PC3
16.  Glycol chitosan nanoparticles as specialized cancer therapeutic vehicles: Sequential delivery of doxorubicin and Bcl-2 siRNA 
Scientific Reports  2014;4:6878.
Conventional chemotherapy is plagued with adverse side effects because cancer treatments are subject to numerous variations, most predominantly from drug resistance. Accordingly, multiple or multistage chemotherapeutic regimens are often performed, combining two or more drugs with orthogonal and possibly synergistic mechanisms. In this respect, glycol chitosan (GC)-based nanoparticles (CNPs) serve as an effective platform vehicle that can encapsulate both chemotherapeutics and siRNA to achieve maximal efficacy by overcoming resistance. Herein, DOX-encapsulated CNPs (DOX-CNPs) or Bcl-2 siRNA-encapsulated CNPs (siRNA-CNPs) exhibited similar physicochemical properties, including size, surface properties and pH sensitive behavior, regardless of the different physical features of DOX and Bcl-2 siRNA. We confirmed that the CNP platform applied to two different types of drugs results in similar in vivo biodistribution and pharmacokinetics, enhancing treatment in a dose-dependent fashion.
PMCID: PMC4217108  PMID: 25363213
17.  Three-Dimensional Amide Proton Transfer MR Imaging of Gliomas: Initial Experience and Comparison with Gadolinium Enhancement 
Journal of magnetic resonance imaging : JMRI  2013;38(5):10.1002/jmri.24067.
To investigate the feasibility of a three-dimensional amide-proton-transfer (APT) imaging sequence with gradient- and spin-echo readouts at 3T in patients with high- or low-grade gliomas.
Materials and Methods
Fourteen patients with newly diagnosed gliomas were recruited. After B0 inhomogeneity correction on a voxel-by-voxel basis, APT-weighted images were reconstructed using a magnetization-transfer-ratio asymmetry at offsets of ±3.5 ppm with respect to the water resonance. Analysis of variance post-hoc tests were used for statistical evaluations, and results were validated with pathology.
In six patients with gadolinium-enhancing high-grade gliomas, enhancing tumors on the post-contrast T1-weighted images were consistently hyperintense on the APT-weighted images. Increased APT-weighted signal intensity was also clearly visible in two pathologically proven, high-grade gliomas without gadolinium enhancement. The average APT-weighted signal was significantly higher in the lesions than in the contralateral normal-appearing brain tissue (P < 0.001). In six low-grade gliomas, including two with gadolinium enhancement, APT-weighted imaging showed iso-intensity or mild punctate hyperintensity within all the lesions, which was significantly lower than that seen in the high-grade gliomas (P < 0.001).
The proposed three-dimensional APT imaging sequence can be incorporated into standard brain MRI protocols for patients with malignant gliomas.
PMCID: PMC3664658  PMID: 23440878
APT imaging; CEST imaging; glioma; tumor grade; gadolinium enhancement
18.  Synthesis and Biological Evaluation of Substrate-Based Imaging Agents for the Prostate-Specific Membrane Antigen 
Macromolecular research  2013;21(5):565-573.
Prostate-specific membrane antigen (PSMA) is an attractive target for the imaging of prostate cancer (PCa) due to the elevated expression on the surface of prostate tumor cells. Most PSMA-targeted low molecular weight imaging agents are inhibitors of PSMA. We have synthesized a series of substrate-based PSMA-targeted imaging agents by mimicking poly-γ-glutamyl folic acid, an endogenous substrate of PSMA. In vitro the γ-linked polyglutamate conjugates proved to be better substrates than the corresponding α-linked glutamates. However, in vivo imaging studies of γ-ray-emitting and γ-linked glutamates did not demonstrate selective uptake in PSMA-pos-itive over PSMA-negative tumors. Subsequent chromatographic studies and in silico molecular dynamics simulations indicated that hydrolysis of the substrates is slow and access to the enzymatic active site is limited. These results inform the design of future substrate-based imaging agents for PSMA.
PMCID: PMC4198338  PMID: 25328507
molecular imaging; prodrug; prostate cancer; SPECT; PSMA
19.  [125I]FIAU imaging in a preclinical model of lung infection: quantification of bacterial load 
2'-Fluoro-2'-deoxy-1β-D-arabinofuranosyl-5-[125I]iodouracil ([125I]FIAU), a substrate for the thymidine kinase (TK) present in most bacteria, has been used as an imaging agent for single photon emission computed tomography (SPECT) in an experimental model of lung infection. Using SPECT-CT we show that [125I]FIAU is specific for bacterial infection rather than sterile inflammation. We report [125I]FIAU lung uptake values of 1.26 ± 0.20 percent injected dose per gram (%ID/g) in normal controls, 1.69 ± 0.32 %ID/g in lung inflammation and up to 7.14 ± 1.09 %ID/g in lung infection in ex vivo biodistribution studies at 24 h after intranasal administration of bacteria. Images of [125I]FIAU signal within lung can be used to estimate the number of bacteria present, with a limit of detection of 109 colony forming units per mL on the X-SPECT scanner. [125I]FIAU-Based bacterial imaging may be useful in preclinical models to facilitate the development of new antibiotics, particularly in cases where a corresponding human trial is planned.
PMCID: PMC3477740  PMID: 23133816
Inflammation; thymidine kinase; nucleoside; SPECT; PET; molecular imaging
20.  68Ga-Labeled Inhibitors of Prostate-Specific Membrane antigen (PSMA) for Imaging Prostate Cancer 
Journal of Medicinal Chemistry  2010;53(14):5333-5341.
Gallium-68 is a generator-produced radionuclide for positron emission tomography (PET) that is being increasingly used for radiolabeling of tumor-targeting peptides. Compounds [68Ga]3 and [68Ga]6 are high-affinity, urea-based inhibitors of the prostate-specific membrane antigen (PSMA) that were synthesized in decay-uncorrected yields ranging from 60 – 70% and radiochemical purities of more than 99%. Compound [68Ga]3 demonstrated 3.78 ± 0.90 percent injected dose per gram of tissue (%ID/g) within PSMA+ PIP tumor at 30 min post-injection, while [68Ga]6 showed a two hour PSMA+ PIP tumor uptake value of 3.29 ± 0.77%ID/g. Target (PSMA+ PIP) to non-target (PSMA− flu) ratios were 4.6 and 18.3, respectively, at those time points. Both compounds delineated tumor clearly by small animal PET. The urea series of imaging agents for PSMA can be radiolabeled with 68Ga, a cyclotron-free isotope useful for clinical PET studies, with maintenance of target specificity.
PMCID: PMC3341619  PMID: 20568777
gallium; molecular imaging; positron emission tomography; prostate-specific membrane antigen; radiopharmaceutical
21.  New Agents and Techniques for Imaging Prostate Cancer 
Journal of Nuclear Medicine  2009;50(9):1387-1390.
The successful management of prostate cancer requires early detection, appropriate risk assessment, and optimum treatment. An unmet goal of prostate cancer imaging is to differentiate indolent from aggressive tumors, as treatment may vary for different grades of the disease. Different modalities have been tested to diagnose, stage, and monitor prostate cancer during therapy. This review briefly describes the key clinical issues in prostate cancer imaging and therapy and summarizes the various new imaging modalities and agents in use and on the horizon.
PMCID: PMC3336101  PMID: 19690043
molecular imaging; MRI; PET; SPECT; radiopharmaceutical
22.  Synthesis and Evaluation of Technetium-99m- and Rhenium-Labeled Inhibitors of the Prostate-Specific Membrane Antigen (PSMA) 
Journal of Medicinal Chemistry  2008;51(15):4504-4517.
The prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for imaging and therapy of cancer. We prepared seven 99mTc/Re-labeled compounds by attaching known Tc/Re chelating agents to an amino-functionalized PSMA inhibitor (lys-NHCONH-glu) with or without a variable length linker moiety. Ki values ranged from 0.17 to 199 nM. Ex vivo biodistribution and in vivo imaging demonstrated the degree of specific binding to engineered PSMA+ PC3 PIP tumors. PC3-PIP cells are derived from PC3 that have been transduced with the gene for PSMA. Despite demonstrating nearly the lowest PSMA inhibitory potency of this series, [99mTc(CO)3(L1)]+ (L1 = (2-pyridylmethyl)2N(CH2)4CH(CO2H)-NHCO-(CH2)6CO-NH-lys-NHCONH-glu) showed the highest, most selective PIP tumor uptake, at 7.9 ± 4.0% injected dose per gram of tissue at 30 min postinjection. Radioactivity cleared from nontarget tissues to produce a PIP to flu (PSMA-PC3) ratio of 44:1 at 120 min postinjection. PSMA can accommodate the steric requirements of 99mTc/Re complexes within PSMA inhibitors, the best results achieved with a linker moiety between the ε amine of the urea lysine and the chelator.
PMCID: PMC3336105  PMID: 18637669
23.  Synthesis and Biological Evaluation of Low Molecular Weight Fluorescent Imaging Agents for the Prostate-Specific Membrane Antigen 
Bioconjugate chemistry  2012;23(12):2377-2385.
Targeted near-infrared (NIR) optical imaging can be used in vivo to detect specific tissues, including malignant cells. A series of NIR fluorescent ligands targeting the prostate-specific membrane antigen (PSMA) was synthesized and each compound was tested for its ability to image PSMA+ tissues in experimental models of prostate cancer. The agents were prepared by conjugating commercially available active esters of NIR dyes, including IRDye800CW, IRDye800RS, Cy5.5, Cy7, or a derivative of indocyanine green (ICG) to the terminal amine group of (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido)pentanedioic acid 1, (14S,18S)-1-amino-8,16-dioxo-3,6-dioxa-9,15,17-triazaicosane-14,18,20-tricarboxylic acid 2 and (3S,7S)-26-amino-5,13,20-trioxo-4,6,12,21-tetraaza-hexacosane-1,3,7,22-tetracarboxylic acid 3. The Ki values for the dye-inhibitor conjugates ranged from 1 to 700 pM. All compounds proved capable of imaging PSMA+ tumors selectively to varying degrees depending on the choice of fluorophore and linker. The highest tumor uptake was observed with IRDye800CW employing a poly(ethylene glycol) or lysine-suberate linker, as in 800CW-2 and 800CW-3, while the highest tumor to nontarget tissue ratios were obtained for Cy7 with these same linkers, as in Cy7-2 and Cy7-3. Compounds 2 and 3 provide useful scaffolds for targeting of PSMA+ tissues in vivo and should be useful for preparing NIR dye conjugates designed specifically for clinical intraoperative optical imaging devices.
PMCID: PMC4131203  PMID: 23157641
25.  Preclinical Evaluation of Novel Glutamate-Urea-Lysine Analogs that Target Prostate Specific Membrane Antigen as Molecular Imaging Pharmaceuticals for Prostate Cancer 
Cancer research  2009;69(17):6932-6940.
Prostate-specific membrane antigen (PSMA) is expressed in normal human prostate epithelium and is highly upregulated in prostate cancer. We previously reported a series of novel small molecule inhibitors targeting PSMA. Two compounds, MIP-1072, (S)-2-(3-((S)-1-carboxy-5-(4–iodobenzylamino)pentyl)ureido)pentanedioic acid and MIP-1095, (S)-2-(3-((S)-1-carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedioic acid, were selected for further evaluation. MIP-1072 and MIP-1095 potently inhibited the glutamate carboxypeptidase activity of PSMA (Ki = 4.6 ± 1.6 and 0.24 ± 0.14 nM, respectively), and when radiolabeled with 123I exhibited high affinity for PSMA on human prostate cancer LNCaP cells (Kd = 3.8 ± 1.3 and 0.81 ± 0.39 nM, respectively). The association of [123I]MIP-1072 and [123I]MIP-1095 with PSMA was specific; there was no binding to human prostate cancer PC3 cells, which lack PSMA, and binding was abolished by co-incubation with a structurally unrelated NAALADase inhibitor, 2-(phosphonomethyl)pentanedioic acid (PMPA). [123I]MIP-1072 and [123I]MIP-1095 internalized into LNCaP cells at 37 °C. Tissue distribution studies in mice demonstrated 17.3 ± 6.3 (at 1 hr) and 34.3 ± 12.7 (at 4 hr) % injected dose per gram of tissue, for [123I]MIP-1072 and [123I]MIP-1095, respectively. [123I]MIP-1095 exhibited greater tumor uptake but slower washout from blood and non-target tissues compared to [123I]MIP-1072. Specific binding to PSMA in vivo was demonstrated by competition with PMPA in LNCaP xenografts, and the absence of uptake in PC3 xenografts. The uptake of [123I]MIP-1072 and [123I]MIP-1095 in tumor bearing mice was corroborated by SPECT/CT imaging. PSMA-specific radiopharmaceuticals should provide a novel molecular targeting option for the detection and staging of prostate cancer.
PMCID: PMC4114247  PMID: 19706750
prostate cancer; molecular imaging; prostate-specific membrane antigen; NAALADase; SPECT

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