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1.  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 
Purpose
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.
Results
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.
Conclusions
These data suggest [18F]DCFPyL as a viable, new positron-emitting imaging agent for PSMA-expressing tissues.
doi:10.1158/1078-0432.CCR-11-1357
PMCID: PMC3243762  PMID: 22042970
PSMA; PET; molecular imaging; prostate cancer; PC3
3.  [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
4.  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.
doi:10.1021/jm100623e
PMCID: PMC3341619  PMID: 20568777
gallium; molecular imaging; positron emission tomography; prostate-specific membrane antigen; radiopharmaceutical
5.  A Modular Strategy to Prepare Multivalent Inhibitors of Prostate-Specific Membrane Antigen (PSMA) 
Oncotarget  2011;2(12):1244-1253.
We have developed a modular scaffold for preparing high-affinity, homo-multivalent inhibitors of the prostate-specific membrane antigen (PSMA) for imaging and therapy of prostate cancer (PCa). Our system contains a lysine-based (∝-, ε-) dialkyne residue for incorporating a PSMA binding Lys-Glu urea motif exploiting click chemistry and a second lysine residue for subsequent modification with an imaging or therapeutic moiety. The utility of the multivalent scaffold was examined by synthesizing bivalent compounds 2 and 3 and comparing them with the monovalent analog 1. Determination of inhibition constants (Ki) revealed that bivalent 2 (0.2 nM) and 3 (0.08 nM) are significantly more potent (~ 5 fold and ~ 11 fold, respectively) inhibitors of PSMA than monovalent 1 (0.9 nM). A single photon emission computed tomography (SPECT)-CT imaging study of [111In]3 demonstrated high and specific uptake in PSMA+ PC-3 PIP tumor until at least 48 h post-injection, with rapid clearance from non-target tissues, including kidney. A biodistribution study revealed that [111In]3 demonstrated 34.0 ± 7.5 percent injected dose per gram of tissue in PSMA+ tumor at 24 h post-injection and was capable of generating target-to-non-target ratios of ~ 379 in PSMA+ PC-3 PIP tumors vs. isogenic PSMA-negative PC3-flu tumors in vivo. The click chemistry approach affords a convenient strategy toward multivalent PSMA inhibitors of enhanced affinity and superior pharmacokinetics for imaging.
PMCID: PMC3282081  PMID: 22207391
Prostate-specific membrane antigen (PSMA); NAALADase; bivalent urea inhibitor; molecular imaging; multivalency; SPECT imaging
6.  Imaging CXCR4 Expression in Human Cancer Xenografts: Evaluation of Monocyclam 64Cu-AMD3465 
The chemokine receptor 4 (CXCR4) is overexpressed in several cancers and metastases and as such presents an enticing target for molecular imaging of metastases and metastatic potential of the primary tumor. CXCR4-based imaging agents could also be useful for diagnosis, staging, and therapeutic monitoring. Here we evaluated a positron-emitting monocyclam analog, 64Cu-{N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine} (64Cu-AMD3465), in subcutaneous U87 brain tumors and U87 tumors stably expressing CXCR4 (U87-stb-CXCR4) and in colon tumors (HT-29) using dynamic and whole-body PET supported by ex vivo biodistribution studies. Both dynamic and whole-body PET/CT studies show specific accumulation of radioactivity in U87-stb-CXCR4 tumors, with the percentage injected dose per gram reaching a maximum of 102.70 ± 20.80 at 60 min and tumor-to-muscle ratios reaching a maximum of 362.56 ± 153.51 at 90 min after injection of the radiotracer. Similar specificity was also observed in the HT-29 colon tumor model. Treatment with AMD3465 inhibited uptake of radioactivity by the tumors in both models. Our results show that 64Cu-AMD3465 is capable of detecting lesions in a CXCR4-dependent fashion, with high target selectivity, and may offer a scaffold for the synthesis of clinically translatable agents.
doi:10.2967/jnumed.110.085613
PMCID: PMC3155288  PMID: 21622896
PET; tumor microenvironment; chemokine; stem cells; molecular imaging; colon cancer; brain cancer; metastasis
7.  Molecular Imaging of CXCR4 Receptor Expression in Human Cancer Xenografts with [64Cu]AMD3100-Positron Emission Tomography 
Cancer research  2010;70(10):3935-3944.
The chemokine receptor CXCR4 and its cognate ligand CXCL12 are pivotal for establishing metastases from many tumor types. Thus, CXCR4 may offer a cell surface target for molecular imaging of metastases, assisting diagnosis, staging and therapeutic monitoring. Further, Noninvasive detection of CXCR4 status of a primary tumor may provide an index of the metastatic potential of the lesion. Here, we report the development and evaluation of a positron-emitting analog of the stem cell mobilizing agent plerixafor, [64Cu]AMD3100, to image this receptor in human tumor xenografts preselected for graded expression of CXCR4. This imaging method was also evaluated in a lung metastases derived from human MDA-MB-231 breast cancer cells. Ex vivo biodistribution studies, performed to validate the in vivo imaging data, confirmed the ability of [64Cu]AMD3100 to image CXCR4 expression. Our findings demonstrate the feasibility of noninvasively imaging CXCR4 by positron emission tomography (PET) using a clinically approved agent as a molecular scaffold.
doi:10.1158/0008-5472.CAN-09-4396
PMCID: PMC2874192  PMID: 20460522
Tumor microenvironment; chemokine receptor; metastasis; molecular imaging; brain tumor; breast cancer
8.  Immunoimaging of CXCR4 expression in brain tumor xenografts using SPECT/CT 
Chemokine receptor 4 (CXCR4) is expressed in a variety of cancers including breast, brain, ovarian and prostate. CXCR4/CXCL12 interactions are critical for tumor development, growth and metastasis. Neoplastic tissue including metastases express high levels of CXCR4 compared to normal tissue. Previous clinical and preclinical observations suggest that CXCR4 levels could be used as a predictive marker of metastatic potential. Here we report single photon emission computed tomography (SPECT)/CT imaging of CXCR4 expression levels in experimental brain tumors using 125I-labeled anti-CXCR4 monoclonal antibodies (rmAbs). hCXCR4 antibody 12G5 and control IgG2A antibody were radiolabeled by the Iodogen method. rmAbs were obtained in 40 – 60% yield, with 1.4 – 1.9 MBq/µg specific radioactivities and >95% purity. SCID mice harboring U87 xenografts were used for ex vivo biodistribution and imaging studies. Surface CXCR4 expression levels on U87 tumor derived cells (U87-TMD) were analyzed by flow cytometry. Biodistribution and imaging studies showed specific accumulation of [125I]12G5 in U87 tumors with tumor/muscle uptake ratios reaching 15 ± 3 at 48 h postinjection. The tumor/tumor uptake ratio for [125I]12G5/[125I]IgG2A was 2.5 at 48 h postinjection. Flow cytometry analysis of tumor derived cells showed 2–7 fold increase in CXCR4 expression relative to inoculums accounting for the high rmAB uptake observed in the tumors. Our data demonstrate the feasibility of imaging CXCR4 expression in experimental brain tumors. The elevated CXCR4 levels observed may have been, in part, due to hypoxic tumor microenvironment.
doi:10.2967/jnumed.108.061325
PMCID: PMC3075860  PMID: 19525448
hypoxia; tumor microenvironment; molecular imaging; xenograft; chemokine
9.  Bioisosterism of Urea-Based GCPII Inhibitors: Synthesis and Structure-Activity Relationships Studies 
We report a strategy based on bioisosterism to improve the physicochemical properties of existing hydrophilic, urea-based GCPII inhibitors. Comprehensive structure-activity relationship studies of the P1’ site of ZJ-43- and DCIBzL-based compounds identified several glutamate-free inhibitors with Ki values below 20 nM. Among them, compound 32d (Ki = 11 nM) exhibited selective uptake in GCPII-expressing tumors by SPECT-CT imaging in mice. A novel conformational change of amino acids in the S1’ pharmacophore pocket was observed in the X-ray crystal structure of GCPII complexed with 32d.
doi:10.1016/j.bmcl.2009.10.061
PMCID: PMC2818328  PMID: 19897367
PSMA; glutamate carboxypeptidase II; molecular imaging; radiopharmaceutical; SPECT
10.  A Low Molecular Weight PSMA-Based Fluorescent Imaging Agent for Cancer 
We synthesized YC-27 3 to provide a fluorescent imaging probe for the prostate-specific membrane antigen (PSMA), a marker for hormone-independent prostate cancer and tumor neovasculature, with suitable pharmacokinetics for use in vivo. Immediate precursor trifluoroacetate salt of 2-(3-{5-[7-(5-amino-1-carboxy-pentylcarbamoyl)-heptanoylamino]-1-carboxy-pentyl}-ureido)-pentanedioic acid 2 was conjugated with a commercially available near-infrared light emitting dye (IRDye 800CW) to provide 3 in 72% yield. YC-27 3 demonstrated a PSMA inhibitory activity of 0.37 nM and was capable of generating target-to-nontarget ratios of at least 10 in PSMA-expressing PC3-PIP vs. PSMA-negative PC3-flu tumors in vivo. YC-27 3 may be useful for study of PSMA-expressing tissue in preclinical models or for intraoperative guidance.
doi:10.1016/j.bbrc.2009.10.017
PMCID: PMC2787846  PMID: 19818734
Prostate-specific membrane antigen; NAALADase; fluorescence; urea; molecular imaging
11.  Synthesis of [125I]IodoDPA-713, a New Probe for Imaging Inflammation 
[125I]IodoDPA-713 [125I]1, which targets the translocator protein (TSPO, 18 KDa), was synthesized in seven steps from methyl-4-methoxybenzoate as a tool for quantification of inflammation in preclinical models. Preliminary in vitro autoradiography and in vivo small animal imaging were performed using [125I]1 in a neurotoxicant-treated rat and in a murine model of lung inflammation, respectively. The radiochemical yield of [125I]1 was 44 ± 6% with a specific radioactivity of 51.8 GBq/μmol (1,400 mCi/μmol) and > 99% radiochemical purity. Preliminary studies showed that [125I]1 demonstrated increased specific binding to TSPO in a neurotoxicant-treated rat and increased radiopharmaceutical uptake in the lungs of an experimental inflammation model of lung inflammation. Compound [125I]1 is a new, convenient probe for preclinical studies of TSPO activity.
doi:10.1016/j.bbrc.2009.08.102
PMCID: PMC2764231  PMID: 19703411
pyrazolopyrimidine; peripheral benzodiazepine receptor; translocator protein; autoradiography; small animal imaging
12.  Radiohalogenated Prostate-Specific Membrane Antigen (PSMA)-Based Ureas as Imaging Agents for Prostate Cancer 
Journal of medicinal chemistry  2008;51(24):7933-7943.
To extend our development of new imaging agents targeting the prostate-specific membrane antigen (PSMA), we have used the versatile intermediate 2-[3-(5-amino-1-carboxy-pentyl)-ureido]-pentanedioic acid (Lys-C(O)-Glu), which allows ready incorporation of radiohalogens for single photon emission computed tomography (SPECT) and positron emission tomography (PET). We prepared 2-[3-[1-carboxy-5-(4-[125I]iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid ([125I]3), 2-[3-[1-carboxy-5-(4-[18F]fluoro-benzoylamino)-pentyl]-ureido]-pentanedioic acid ([18F]6) and 2-(3-[1-carboxy-5-[(5-[125I]iodo-pyridine-3-carbonyl)-amino]-pentyl]-ureido)-pentanedioic acid ([125I]8) in 65 - 80% (non-decay-corrected), 30 - 35% (decay corrected) and 59 - 75% (non-decay-corrected) radiochemical yields. Compound [125I]3 demonstrated 8.8 ± 4.7 percent injected dose per gram (%ID/g) within PSMA+ PC-3 PIP tumor at 30 min postinjection, which persisted, with clear delineation of the tumor by SPECT. Similar tumor uptake values at early time points were demonstrated for [18F]6 (using PET) and [125I]8. Because of the many radiohalogenated moieties that can be attached via the ε amino group, the intermediate Lys-C(O)-Glu is an attractive template upon which to develop new imaging agents for prostate cancer.
doi:10.1021/jm801055h
PMCID: PMC2631656  PMID: 19053825
NAALADase; GCPII; radiopharmaceutical; SPECT; PET; small animal imaging

Results 1-12 (12)