PT  - JOURNAL ARTICLE
AU  - Svetlana N. Rylova
AU  - Beatrice Waser
AU  - Luigi Del Pozzo
AU  - Roswitha Tönnesmann
AU  - Rosalba Mansi
AU  - Philipp T. Meyer
AU  - Jean Claude Reubi
AU  - Helmut R. Maecke
TI  - Approaches to Improve the Pharmacokinetics of Radiolabeled Glucagon-Like Peptide-1 Receptor Ligands Using Antagonistic Tracers
AID  - 10.2967/jnumed.115.168948
DP  - 2016 Aug 01
TA  - Journal of Nuclear Medicine
PG  - 1282--1288
VI  - 57
IP  - 8
4099  - http://jnm.snmjournals.org/content/57/8/1282.short
4100  - http://jnm.snmjournals.org/content/57/8/1282.full
SO  - J Nucl Med2016 Aug 01; 57
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.