RT Journal Article
SR Electronic
T1 Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1282
OP 1288
DO 10.2967/jnumed.115.168948
VO 57
IS 8
A1 Svetlana N. Rylova
A1 Beatrice Waser
A1 Luigi Del Pozzo
A1 Roswitha Tönnesmann
A1 Rosalba Mansi
A1 Philipp T. Meyer
A1 Jean Claude Reubi
A1 Helmut R. Maecke
YR 2016
UL http://jnm.snmjournals.org/content/57/8/1282.abstract
AB The glucagon-like peptide-1 (GLP-1) receptors are important biomarkers for imaging pancreatic β-cell mass and detection of benign insulinomas. Using GLP-1 receptor antagonists, we aimed to eliminate the insulin-related side effects reported for all GLP-1 receptor agonists. Additionally, using a nonresidualizing tracer, 125I-Bolton-Hunter-Exendin(9-39)NH2 (125I-BH-Ex(9-39)NH2), we aimed to reduce the high kidney uptake, enabling a better detection of insulinomas in the tail and head of the pancreas. Methods: The affinity and biodistribution of Ex(9-39)NH2-based antagonists, modified with DOTA or NODAGA chelators at positions Lys27 and Lys40 and labeled with 68Ga and 125I-BH-Ex(9-39)NH2, were compared with the reference GLP-1 receptor agonist [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4. The inhibitory concentration of 50% (IC50) values were determined using autoradiography on human tissues with 125I-GLP-1(7-36)NH2 as a radioligand. Pharmacokinetics and PET imaging were studied in nude mice bearing rat Ins-1E tumors. Results: Conjugation of DOTA and NODAGA chelators at positions Lys27 and Lys40 of Ex(9-39)NH2 resulted in a distinct loss of affinity toward GLP-1 receptor in vitro. Among the studied antagonists, [Lys40(NODAGA-natGa)NH2]Ex(9-39) showed the lowest IC50 value (46.7 ± 16.3 nM). The reference agonist [Nle14,Lys40(Ahx-DOTA)NH2]Ex-4 demonstrated the highest affinity (IC50 = 0.9 ± 0.3 nM). Biodistribution of [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]Ex-4 at 1 h after injection demonstrated 40.2 ± 8.2 percentage injected activity per gram (%IA/g) uptake in Ins-1E tumor, 12.5 ± 2.2 %IA/g in the pancreas, and 235.8 ± 17.0 %IA/g in the kidney, with tumor-to-blood and tumor-to-kidney ratios of 100.52 and 0.17, respectively. Biodistribution of [Lys40(NODAGA-68Ga)NH2]Ex(9-39) showed only 2.2 ± 0.2 %IA/g uptake in Ins-1E tumor, 1.0 ± 0.1 %IA/g in the pancreas, and 78.4 ± 8.5 %IA/g in the kidney at 1 h after injection, with tumor-to-blood and tumor-to-kidney ratios of 7.33 and 0.03, respectively. In contrast, 125I-BH-Ex(9-39)NH2 showed tumor uptake (42.5 ± 8.1 %IA/g) comparable to the agonist and 28.8 ± 5.1 %IA/g in the pancreas at 1 h after injection. As we hypothesized, the kidney uptake of 125I-BH-Ex(9-39)NH2 was low, only 12.1 ± 1.4 %IA/g at 1 h after injection. The tumor-to-kidney ratio of 125I-BH-Ex(9-39)NH2 was improved 20-fold. Conclusion: Our results suggest that iodinated Ex(9-39)NH2 may be a promising tracer for imaging GLP-1 receptor expression in vivo. Because of the 20-fold improved tumor-to-kidney ratio 125I-BH-Ex(9-39)NH2 may offer higher sensitivity in the detection of insulinomas and imaging of β-cell mass in diabetic patients. Further studies with 124I-BH-Ex(9-39)NH2 are warranted.