TY - JOUR
T1 - PET of insulinoma using 18F-FBEM-EM3106B, a new GLP-1 analogue
AU - Gao, Haokao
AU - Niu, Gang
AU - Yang, Min
AU - Quan, Qimeng
AU - Ma, Ying
AU - Murage, Eunice N.
AU - Ahn, Jung Mo
AU - Kiesewetter, Dale O.
AU - Chen, Xiaoyuan
PY - 2011/10/3
Y1 - 2011/10/3
N2 - Derived from endocrine pancreatic beta cells, insulinomas express glucagon-like peptide-1 (GLP-1) receptor with high density and incidence. In this study, we labeled a novel GLP-1 analogue, EM3106B, with 18F and performed PET imaging to visualize insulinoma tumors in an animal model. A GLP-1 analogue that contains multiple lactam bridges, EM3106B, was labeled with 18F through a maleimide-based prosthetic group, N-2-(4- 18F-fluorobenzamido)ethylmaleimide (18F-FBEM). The newly developed radiotracer was characterized by cell based receptor-binding assay, cell uptake and efflux assay. The stability in serum was evaluated by radio-HPLC analysis. In vivo PET imaging was performed in nude mice bearing subcutaneous INS-1 insulinoma tumors and MDA-MB-435 tumors of melanoma origin. Ex vivo biodistribution study was performed to confirm the PET imaging data. EM3106B showed high binding affinity (IC50 = 1.38 nM) and high cell uptake (5.25 ± 0.61% after 120 min incubation). 18F-FBEM conjugation of EM3106B resulted in high labeling yield (24.9 ± 2.4%) and high specific activity (>75 GBq/μmol at the end of bombardment). EM3106B specifically bound and was internalized by GLP-1R positive INS-1 cells. After intravenous injection of 3.7 MBq (100 μCi) of 18F-FBEM-EM3106B, the INS-1 tumors were clearly visible with high contrast in relation to the contralateral background on PET images, and tumor uptake of 18F-FBEM- EM3106B was determined to be 28.5 ± 4.7 and 25.4 ± 4.1% ID/g at 60 and 120 min, respectively. 18F-FBEM-EM3106B showed low uptake in MB-MDA-435 tumors with low level of GLP-1R expression. Direct tissue sampling biodistribution experiment confirmed high tracer uptake in INS-1 tumors and receptor specificity in both INS-1 tumor and pancreas. In conclusion, 18F-FBEM-EM3106B exhibited GLP-1R-receptor-specific targeting properties in insulinomas. The favorable characteristics of 18F-FBEM- EM3106B, such as high specific activity and high tumor uptake, and high tumor to nontarget uptake, demonstrate that it is a promising tracer for clinical insulinoma imaging.
AB - Derived from endocrine pancreatic beta cells, insulinomas express glucagon-like peptide-1 (GLP-1) receptor with high density and incidence. In this study, we labeled a novel GLP-1 analogue, EM3106B, with 18F and performed PET imaging to visualize insulinoma tumors in an animal model. A GLP-1 analogue that contains multiple lactam bridges, EM3106B, was labeled with 18F through a maleimide-based prosthetic group, N-2-(4- 18F-fluorobenzamido)ethylmaleimide (18F-FBEM). The newly developed radiotracer was characterized by cell based receptor-binding assay, cell uptake and efflux assay. The stability in serum was evaluated by radio-HPLC analysis. In vivo PET imaging was performed in nude mice bearing subcutaneous INS-1 insulinoma tumors and MDA-MB-435 tumors of melanoma origin. Ex vivo biodistribution study was performed to confirm the PET imaging data. EM3106B showed high binding affinity (IC50 = 1.38 nM) and high cell uptake (5.25 ± 0.61% after 120 min incubation). 18F-FBEM conjugation of EM3106B resulted in high labeling yield (24.9 ± 2.4%) and high specific activity (>75 GBq/μmol at the end of bombardment). EM3106B specifically bound and was internalized by GLP-1R positive INS-1 cells. After intravenous injection of 3.7 MBq (100 μCi) of 18F-FBEM-EM3106B, the INS-1 tumors were clearly visible with high contrast in relation to the contralateral background on PET images, and tumor uptake of 18F-FBEM- EM3106B was determined to be 28.5 ± 4.7 and 25.4 ± 4.1% ID/g at 60 and 120 min, respectively. 18F-FBEM-EM3106B showed low uptake in MB-MDA-435 tumors with low level of GLP-1R expression. Direct tissue sampling biodistribution experiment confirmed high tracer uptake in INS-1 tumors and receptor specificity in both INS-1 tumor and pancreas. In conclusion, 18F-FBEM-EM3106B exhibited GLP-1R-receptor-specific targeting properties in insulinomas. The favorable characteristics of 18F-FBEM- EM3106B, such as high specific activity and high tumor uptake, and high tumor to nontarget uptake, demonstrate that it is a promising tracer for clinical insulinoma imaging.
KW - F-FBEM
KW - PET
KW - bicyclic GLP-1 analogue
KW - glucagon-like peptide-1 receptor
KW - insulinoma
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U2 - 10.1021/mp200141x
DO - 10.1021/mp200141x
M3 - Article
C2 - 21800885
AN - SCOPUS:80053493999
SN - 1543-8384
VL - 8
SP - 1775
EP - 1782
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 5
ER -