New PET probes show promise
The success of the PET tracer FDG, along with an established and emergent worldwide PET infrastructure, is generating greater interest in the detection of tumor response to therapy, according to a review of new PET agents in the May supplement issue of the Journal of Nuclear Medicine.
Mark P.S. Dunphy, DO, from the department of radiology, nuclear medicine service at Memorial Sloan-Kettering Cancer Center and Jason S. Lewis, PhD, chief of the radiochemistry service at the Sloan Kettering Institute for Cancer Research in New York City covered non–18F-FDG PET tracers that are in the final stages of preclinical development or in the early stages of clinical application for monitoring the therapeutic response.
“In the coming decade, cancer care specialists can look forward to a wave of noninvasive molecular probes other than 18F-FDG for predicting and characterizing the tumor response to therapy in new ways that are more specific to the therapeutic regimens used,” wrote Dunphy and Lewis.
The thymidine analogs 18F-fluoro-deoxythymidine (18F-FLT) and 18F-deoxy-fluoro-arabinofuranosylthymine (18F-FMAU) were noted by Dunphy and Lewis as two of the most promising agents for tumor imaging.
“18F-FLT PET provides data on TK1 activity and an index of cell cycling and tissue proliferation, an 18F-FMAU PET provides data on TK2 activity and an index of mitochondrial mass in a tissue,” they wrote.
Because TK1 and TK2 are independent enzymes, each tracer has the capability to provide different types of information to diagnosticians. The authors observed that tumors often do not concentrate 18F-FLT as avidly as 18F-FDG, which can be of benefit for tumor delineation in some viscera and anatomic regions; such as the brain, mediastinum (including the heart) and intestines. 18F-FMAU has clearly visualized tumors (11 minutes after injection) in the breasts, brain, lungs and prostate in a pilot study, demonstrating that it may be a useful tumor imaging option.
Tumor hypoxia is an important determinant of the overall response of a tumor to conventional therapy. It is associated with increased tumor aggressiveness, manifested as higher rates of recurrence and metastasis and resistance to chemotherapy. Therefore, the authors noted, the imaging of tumor hypoxia could result in a significant improvement in the care of patients with cancer.
Two PET agents, Cu-labeled diacetyl-bis methylthiosemicarbazone (Cu-ATSM) and 18F- fluoromisonidazole (18F-FMISO), are currently the leading candidates for hypoxia imaging. Pilot studies conducted with Cu-ATSM have demonstrated that the agent shows high contrast levels between hypoxic and normoxic tissues in as little as 10 to 15 minutes post-injection.
“Cu-ATSM has several well known advantages over other radiopharmaceuticals used for PET of hypoxia , including a simpler method for synthesis, faster clearance from normoxic tissue (allowing a short time between injection and imaging), and a simpler method for quantification,” wrote Dunphy and Lewis.
The most extensively studied radiolabeled nitroimidazole (a class of compounds whose metabolism and tissue retention are dependent on tissue oxygenation) for in vivo PET
is 18F-FMISO, which is lipophilic and therefore diffuses readily through cell membranes, the authors noted.
“The main advantage of 18F-FMISO is that it is directly affected by tumor oxygenation, but the compound has two major limitations,” wrote Dunphy and Lewis. “One is the limited contrast ratio between hypoxic tumors and normal tissues (T/B ratio of >1.2), reflecting the poor tissue uptake of 18F-FMISO in vivo. The other is the slow cellular washout of this tracer; a delay of approximately two hours after the injection of 18F-FMISO is needed to permit the clearance of this tracer from normal background tissues.”
Another PET agent area under development is amino acid tracers, with 11C-methionine (11C-MET) being the most popular in oncology imaging. Although the compound has demonstrated great efficacy in differentiating tumor recurrence from radiation necrosis (useful for managing irradiated brain tumors), its short half-life has limited widespread use.
Also under investigation are agents for hormone receptor imaging in evaluating breast and prostate cancer such as 18F-fluoro-dihydrotestosterone (18F-FDHT) and 18F-fluoro-estradiol (18F-FES). In addition, 11C-labled therapeutic drugs as well as 11C-Acetate and 11C-Choline PET agents are receiving more investigative interest.
“These clinical PET tools should improve therapeutic planning and response assessment and should lead to improved patient outcomes,” observed Dunphy and Lewis.
Mark P.S. Dunphy, DO, from the department of radiology, nuclear medicine service at Memorial Sloan-Kettering Cancer Center and Jason S. Lewis, PhD, chief of the radiochemistry service at the Sloan Kettering Institute for Cancer Research in New York City covered non–18F-FDG PET tracers that are in the final stages of preclinical development or in the early stages of clinical application for monitoring the therapeutic response.
“In the coming decade, cancer care specialists can look forward to a wave of noninvasive molecular probes other than 18F-FDG for predicting and characterizing the tumor response to therapy in new ways that are more specific to the therapeutic regimens used,” wrote Dunphy and Lewis.
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| Newly diagnosed glioblastoma. (A) MRI (contrast-enhanced T1-weighted image) shows large area of contrast enhancement in right frontal lobe. (B and C) Both 18-FDG PET (B) and 18F-FLT PET (C) show increased uptake in same area. Image and caption courtesy of |
The thymidine analogs 18F-fluoro-deoxythymidine (18F-FLT) and 18F-deoxy-fluoro-arabinofuranosylthymine (18F-FMAU) were noted by Dunphy and Lewis as two of the most promising agents for tumor imaging.
“18F-FLT PET provides data on TK1 activity and an index of cell cycling and tissue proliferation, an 18F-FMAU PET provides data on TK2 activity and an index of mitochondrial mass in a tissue,” they wrote.
Because TK1 and TK2 are independent enzymes, each tracer has the capability to provide different types of information to diagnosticians. The authors observed that tumors often do not concentrate 18F-FLT as avidly as 18F-FDG, which can be of benefit for tumor delineation in some viscera and anatomic regions; such as the brain, mediastinum (including the heart) and intestines. 18F-FMAU has clearly visualized tumors (11 minutes after injection) in the breasts, brain, lungs and prostate in a pilot study, demonstrating that it may be a useful tumor imaging option.
Tumor hypoxia is an important determinant of the overall response of a tumor to conventional therapy. It is associated with increased tumor aggressiveness, manifested as higher rates of recurrence and metastasis and resistance to chemotherapy. Therefore, the authors noted, the imaging of tumor hypoxia could result in a significant improvement in the care of patients with cancer.
Two PET agents, Cu-labeled diacetyl-bis methylthiosemicarbazone (Cu-ATSM) and 18F- fluoromisonidazole (18F-FMISO), are currently the leading candidates for hypoxia imaging. Pilot studies conducted with Cu-ATSM have demonstrated that the agent shows high contrast levels between hypoxic and normoxic tissues in as little as 10 to 15 minutes post-injection.
“Cu-ATSM has several well known advantages over other radiopharmaceuticals used for PET of hypoxia , including a simpler method for synthesis, faster clearance from normoxic tissue (allowing a short time between injection and imaging), and a simpler method for quantification,” wrote Dunphy and Lewis.
The most extensively studied radiolabeled nitroimidazole (a class of compounds whose metabolism and tissue retention are dependent on tissue oxygenation) for in vivo PET
is 18F-FMISO, which is lipophilic and therefore diffuses readily through cell membranes, the authors noted.
“The main advantage of 18F-FMISO is that it is directly affected by tumor oxygenation, but the compound has two major limitations,” wrote Dunphy and Lewis. “One is the limited contrast ratio between hypoxic tumors and normal tissues (T/B ratio of >1.2), reflecting the poor tissue uptake of 18F-FMISO in vivo. The other is the slow cellular washout of this tracer; a delay of approximately two hours after the injection of 18F-FMISO is needed to permit the clearance of this tracer from normal background tissues.”
Another PET agent area under development is amino acid tracers, with 11C-methionine (11C-MET) being the most popular in oncology imaging. Although the compound has demonstrated great efficacy in differentiating tumor recurrence from radiation necrosis (useful for managing irradiated brain tumors), its short half-life has limited widespread use.
Also under investigation are agents for hormone receptor imaging in evaluating breast and prostate cancer such as 18F-fluoro-dihydrotestosterone (18F-FDHT) and 18F-fluoro-estradiol (18F-FES). In addition, 11C-labled therapeutic drugs as well as 11C-Acetate and 11C-Choline PET agents are receiving more investigative interest.
“These clinical PET tools should improve therapeutic planning and response assessment and should lead to improved patient outcomes,” observed Dunphy and Lewis.