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.
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.
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.
One reagent for two techniques: Compound [111In]1 provides a platform for sequential radionuclide and optical imaging of prostate cancer through targeting of the prostate‐specific membrane antigen. Because the same subject can be dual‐imaged after one injection of the agent, these findings support rapid clinical translation.
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.
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.
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