Over the past several years, Positron Emission Tomography (PET) imaging agents labeled with ;68Gallium (68Ga) have undergone a significant increase in clinical utilization. 68Ga is conveniently produced from a germanium-68/gallium-68 (68Ge/68Ga) generator. Because of the compact size and ease of use of the generator, 68Ga labeled compounds may be more cost-effective than PET radioisotopes that are cyclotron-produced. The convenient half-life of 68Ga (T1/2=68 min) provides sufficient radioactivity for various PET imaging applications, while delivering acceptable radiation doses to patients. This chapter summarizes the emerging clinical utilization of 68Ga-based radiotracers in medical imaging.
Introduction Early detection of pancreatic cancer could save many thousands of lives. Non-invasive diagnostic imaging, including PET with [18F]FDG, have inadequate resolution for detection of small (2–3 mm) pancreatic tumors. We demonstrated the efficacy of PET imaging with an 18F-labeled lactose derivative, [18F]FEDL, that targets HIP/PAP, a biomarker that is overexpressed in the peritumoral pancreas. We developed another analogue, 1-[18F]fluoroethyl lactose ([18F]FEL), which is simpler to synthesize, for the same application. We conducted a preliminary evaluation of the new probe and its efficacy in detecting orthotopic pancreatic carcinoma xenografts in mice. Methods Xenografts were developed in nude mice by injecting L3.6pl/GL+ pancreatic carcinoma cells into the pancreas of each mouse. Tumor growth was monitored by bioluminescence imaging (BLI); accuracy of BLI tumor size estimates was verified by MRI in two representative mice. When the tumor size reached approximately 2–3 mm, the animals were injected with [18F]FEL (3.7 MBq) and underwent static PET/CT scans. Blood samples were collected at 2, 5, 10, 20 and 60 min after [18F]FEL injection to track blood clearance. Following imaging, animals were sacrificed and their organs and tumors/pancreatic tissue were collected and counted on a gamma counter. Pancreas, including tumor, was frozen, sliced and used for autoradiography and immunohistochemical analysis of HIP/PAP expression. Results Tumor growth was rapid, as observed by BLI and MRI. Blood clearance of [18F]FEL was bi-exponential, with half-lives of approximately 3.5 min and 40 min. Mean accumulation of [18F]FEL in the peritumoral pancreatic tissue was 1.29±0.295 %ID/g, and that in the normal pancreas of control animals was 0.090±0.101 %ID/g. [18F]FEL was cleared predominantly by the kidneys. Comparative analysis of autoradiographic images and immunostaining results demonstrated a correlation between [18F]FEL binding and HIP/PAP expression. Conclusion [18F]FEL may be useful for non-invasive imaging of early-stage pancreatic tumors by PET. The results warrant further studies.
Early detection of pancreatic cancer has been a long-standing challenge in determining prognosis and management of the deadly disease. Although the incidence of pancreatic cancer is low (2% of all malignancies), it is the fourth leading cause of deaths attributable to cancer in the U.S. A major cause for the high mortality rate, which exceeds 85%, is the difficulty in diagnosing the disease early in its development. The relative lack of reliable diagnostic tools to screen patients who are asymptomatic prior to the aggressive progression of disease has been the primary contributing factor in the high mortality rate in this patient population. Indeed, 80-90% of patients with pancreatic cancer have relatively small unresectable tumors at the time of diagnosis. Therefore, there is an unmet need for a highly sensitive diagnostic imaging modality to detect early-stage pancreatic cancer, as this may save the lives of many thousands of patients. Many literature reviews have been published on various aspects of pancreatic cancer, including biology, screening, and therapy; however, limited information is available on early detection, especially the use of highly sensitive modalities such as positron emission tomography (PET). Current [(18)F]FDG/PET imaging combined with CT (PET/CT) lacks the necessary sensitivity and specificity for detection of small lesions (~2-3 mm) of pancreatic cancer that may be resectable and curable. Furthermore, accumulation of [(18)F]FDG in inflammatory tissue is a major problem; therefore, an appropriate PET tracer that is both highly sensitive and specific for carcinoma is necessary for PET imaging of early stage pancreatic cancer. This review focuses on early detection of pancreatic cancer by PET, including new targets and the development and application of new PET tracers.
Introduction 1′-[18 F]Fluoroethyl-β-d-lactose ([18 F]FEL) is a new PET imaging agent for early detection of pancreatic cancer and hepatocellular carcinoma. We previously reported the syntheses of [18 F]FEL using a bromo- and a tosyl- precursor, followed by an improved method using a nosyl-precursor. However, some steps in the synthesis of the precursor appeared to be problematic producing low yields. Here, we report on an optimized method for synthesis of the precursor and production of [18 F]FEL; we also describe [18 F]FEL’s formulation and stability. Methods Acetylation of d-lactose 1 was performed following a literature procedure to obtain 1′,2′,3′,6′,2,3,4,6-d-lactose octa-acetate 2a/2b. Bromination of 2a/2b was performed using HBr/acetic acid to produce 1'-bromo-2′,3′,6′,2,3,4,6-hepta-O-acetyl-α-d-lactose 3. Coupling of 3 with ethylene glycol was performed in the presence of Ag-tosylate and an excess of ethylene glycol to produce 4a. Compound 4a was reacted with p-nitrophenylsulfonyl chloride to produce the nosyl derivative 5. Radiofluorination of 5 was performed using K[18 F]fluoride/kryptofix to obtain 6, which was purified by HPLC and hydrolyzed with Na-methoxide to produce 7. Results Compound 2 (2a/2b) was obtained in 83% yield as a mixture of two anomeric products. Compound 3 was obtained from the 2a/2b mixture in 80% yield as one product. Coupling of 3 with ethylene glycol produced 4a in 90% yield. Compound 5 was obtained in 64% yield, and radiofluorination of 5 produced 6 in 62.5% ± 7.5% yields (n = 8). Hydrolysis of 6 with Na-methoxide produced 7 in 42.0% ± 7.0% yield (n = 8) from the end of bombardment. Conclusions A simple 4-step synthesis of the precursor, compound 5, has been achieved with improved yields. A new formulation of [18 F]FEL has been developed that allows the product to remain stable at ambient temperature for use in animal studies. This improved synthesis of the precursor and stable formulation of [18 F]FEL should be useful for routine production of the radiotracer and its preclinical and, possibly, clinical applications.
Background: CDH3 gene overexpression of P-cadherin correlates with increased tumor cell invasiveness and is observed in breast, colon, lung, and pancreatic tumors. FF-21101 is a human-mouse chimeric monoclonal antibody directed against P-cadherin, conjugated with 111In for dosimetry and 90Y for therapy. This first-in-human study assesses dosimetry (biodistribution) and therapeutic outcome of FF-21101(90Y). Methods: For dosimetry, patients (pts) received 5 mCi/5mg FF-21101(111In) 1 week before the FF-21101(90Y) therapeutic dose to assess biodistribution and ensure 90Y radiation dose estimates did not exceed the recommended allowable limit for each organ. Single therapeutic dose cohorts were planned for FF-21101(90Y) (8 mCi/mg) at 5, 10, 15, 20 or 25 mCi/m2 (3+3 dose escalation schema), with repeat doses allowed every 4 cycles. Disease assessments were based on RECIST V1.1. Pre-treatment tumor samples were assessed for P-cadherin expression by immunohistochemistry (IHC). Pharmacokinetics (PK) of FF-21101 also were assessed. Results: Seven pts (3M, 4F) with advanced primary solid tumors and loco-regional metastases were treated with FF-21101(90Y) in the first 3 dose cohorts. Median (range) values: age 55 years (31 – 69), number of prior treatments, including surgery, radiation and/or chemotherapy 5 (2 – 8); tumor types: ovarian carcinoma (CA) (2 pts), vaginal CA, pancreatic neuroendocrine tumor (PNET), desmoplastic small round cell (DSRC) tumor, colorectal CA (CRC), recurrent liposarcoma (1 pt each). Primary and/or metastatic tumors from 4 of 7 pts (57.1%) demonstrated positive uptake of FF-21101(111In). Highest uptake was seen in epithelial tumors, consistent with P-cadherin targeting. Median (range) time on study following the FF-21101(90Y) dose was 8 (4 – 40) weeks. The vaginal CA pt demonstrated an 18.5% decrease as best response through 16 weeks following a single therapeutic dose. A viable pre-study tumor sample was not available for IHC staining. Pre-treatment tumor samples available from 6 of 7 patients demonstrated high H scores (≥ 100) in 3 pts (50%); 2 ovarian and 1 PNET; all remain on study through 4, 12 and 40 weeks, respectively, thus demonstrating the potential predictive utility of pre-treatment tumor P-cadherin expression. FF-21101(90Y) has been well-tolerated. Drug-related adverse events (AEs) include Gr 1 rash (1 pt) and increased AST (Gr 1/2, 2 pts) at 5 mCi/m2, and lymphopenia (1 Gr 3 in 3 pts at 10 mCi/m2), all reversible. There have been no drug-related serious AEs. Mean FF-21101 Cmax and AUC0-t increased with dose, suggesting linear PK. Conclusions: Tumor P-cadherin overexpression provides an attractive target for radioimmunotherapy. FF-21101(111In/90Y) exhibits favorable dosimetry, good tolerability and preliminary evidence of reduction in tumor burden. Pre-treatment tumor P-cadherin expression may be an important biomarker for patient selection. Citation Format: Vivek Subbiah, William Erwin, Osama Mawlawi, Carlos Gonzalez Lepera, Masahiko Tokura, Masayuki Kawakami, Holly Liu, Shubham Pant, Michele Rosner, Mary Johansen, Louis De Palatis, Thomas Myers, Linda Paradiso, Elmer Santos, Gregory Ravizzini. Phase 1 study of FF-21101(90Y), a radioimmunotherapeutic targeting P-cadherin, in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT097. doi:10.1158/1538-7445.AM2017-CT097
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