Development of an ¹¹¹In-Labeled Glucagon-Like Peptide-1 Receptor-Targeting Exendin-4 Derivative that Exhibits Reduced Renal Uptake

Abstract

Insulinomas are neuroendocrine tumors that are mainly found in the pancreas. Surgical resection is currently the first-line treatment for insulinomas; thus, it is vital to preoperatively determine their locations. The marked expression of the glucagonlike peptide-1 receptor (GLP-1R) is seen in pancreatic β-cells and almost all insulinomas. Radiolabeled derivatives of exendin-4, a GLP-1R agonist, have been used with nuclear medicine imaging techniques for the in vivo detection of the GLP-1R; however, their marked renal accumulation can hinder the imaging of pancreatic tail lesions. To develop a GLP-1R imaging probe that exhibits reduced renal accumulation, we designed and synthesized a straight-chain GLP-1R-targeting radioligand, [ 111 In]In-E4DA1, which consisted of exendin-4, DOTADG (a chelator), and an (iodophenyl)butyric acid derivative (an albumin binder [ALB]). We performed preclinical evaluations of [ 111 In]In-E4DA1 to investigate its utility as a GLP-1R imaging probe. [ 111 In]In-E4DA1 and [ 111 In]In-E4D (a control compound lacking the ALB moiety) were prepared by reacting the corresponding precursors with [ 111 In]InCl 3 in buffer. Cell-binding and human serum albumin (HSA)-binding assays were performed to assess the in vitro affinity of the molecules for INS-1 (GLP-1R-positive) cells and albumin, respectively. A biodistribution assay and single-photon emission computed tomography imaging were carried out using INS-1 tumorbearing mice. In the cell-binding assay, [ 111 In]In-E4DA1 and [ 111 In]In-E4D exhibited in vitro binding to INS-1 cells. In the HSAbinding assay, [ 111 In]In-E4DA1 bound to HSA, while [ 111 In]In-E4D showed little HSA binding. The in vivo experiments involving INS-1 tumor-bearing mice revealed that the introduction of an ALB moiety into the DOTADG-based exendin-4 derivative markedly increased the molecule's tumor accumulation while decreasing its renal accumulation. In addition, [ 111 In]In-E4DA1 exhibited greater tumor accumulation than renal accumulation, whereas previously reported radiolabeled exendin-4 derivatives demonstrated much higher accumulation in the kidneys than in tumors. These results indicate that [ 111 In]In-E4DA1 may be a useful GLP-1R imaging probe, as it demonstrates only slight renal accumulation.

Preclinical investigations using [177Lu]Lu-Ibu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer

“…Radiopharmaceuticals with commonly high kidney uptake, including folate radioconjugates or glucagon-like peptide-1-based radiopeptides, showed reduced renal retention after modification with an albumin binder [31][32][33]. This was, however, not the case for [ 177 Lu]Lu-Ibu-DAB-PSMA and [ 177 Lu]Lu-PSMA-ALB-56 or any other albumin-binding PSMA radioligand [10,12,14,28], which all showed higher kidney retention than [ 177 Lu]Lu-PSMA-617.…”

Structure–Activity Relationships and Pharmacokinetics of 111In-Labeled Glucagon-like Peptide-1 Receptor-Targeting Exendin-4 Derivatives Conjugated with Albumin Binder Moieties

“…In our previous study, [ 111 In]­In-E4DA1 was synthesized via a thiol–maleimide coupling reaction (exendin-4 conjugation) before being subjected to 111 In-labeling . On the other hand, in this study, the synthesis of [ 111 In]­In-E4DA1–4 was accomplished in two steps: the prelabeling of 5 – 8 with 111 In followed by a thiol–maleimide coupling reaction.…”

“…These results indicate that the substituted groups within ALB moieties markedly modify the pharmacokinetics of radioligands based on the middle-molecule exendin-4, as well as those of small-molecule-based radioligands. We previously described an 111 In-labeled DOTADG-based exendin-4 derivative without an ALB moiety ([ 111 In]­In-E4D) . The tumor AUC value for [ 111 In]­In-E4D was 1051% ID/g·h, indicating that the introduction of the ALB moiety markedly enhanced the tumor accumulation of all of the exendin-4-based radioligands, except for [ 111 In]­In-E4DA4.…”

“…Recently, low-molecular-weight albumin binder (ALB) entities, e.g ., 4-(4-iodophenyl)­butyric acid and Evans blue derivatives, have been introduced into radioligands to improve the pharmacokinetics of the radioligands . ALB-conjugated radioligands, in which endogenous albumin was used as a reversible carrier for drug delivery, showed enhanced tumor accumulation and reduced renal accumulation compared with their non-ALB-conjugated counterparts. , Recently, we reported a unique radioligand design based on a 1,4,7,10-tetraazacyclododecane-1,7-(diacetic acid)-4,10-diglutaric acid (DOTADG) chelator, which enables the easy introduction of an ALB moiety. − DOTADG can be labeled with various radiometals, e.g ., 177 Lu and 225 Ac, and the resultant complexes exhibit favorable stability. , In particular, an 111 In-labeled exendin-4 derivative based on a DOTADG chelator ([ 111 In]­In-E4DA1) (Figure ), which contained a 4-(4-iodophenyl)­butyric acid derivative as an ALB moiety, showed markedly enhanced tumor uptake and reduced renal accumulation compared with its counterpart without an ALB moiety . In addition, the tumor accumulation of [ 111 In]­In-E4DA1 was over 2-fold higher than its renal accumulation at all evaluated time points, and clear tumor imaging, with only slight radioactivity within normal tissues, was achieved by performing SPECT with [ 111 In]­In-E4DA1.…”

“…In this study, we designed 111 In-labeled exendin-4-based DOTADG derivatives containing 4-(4-substituted phenyl)-moieties as ALB moieties ([ 111 In]­In-E4DA2–4) (Figure ). In our previous study, we prepared [ 111 In]­In-E4DA1 by subjecting an exendin-4-conjugated precursor to 111 In-labeling (a postlabeling method); however, the 111 In-labeled product could not be easily separated from the precursor . Thus, in this study, we prepared [ 111 In]­In-E4DA2–4 using a prelabeling method ( 111 In-labeling was performed before exendin-4 conjugation).…”