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.

The indentation crack has been used as a model of surface flaw in the strength tests of ceramics. In evaluation of such strength properties, some attention should be paid to the residual stress effect due to indentation. In this study, fatigue crack growth behavior from indentation flaws was investigated in sintered silicon nitride and alumina. In both materials, a V-shaped behavior was observed in the relation between the maximum stress intensity factor and the crack growth rate. The indentation crack was analyzed using fracture mechanics procedure to take account of the residual component. On the basis of the analysis, an effective stress intensity factor for crack growth was successfully evaluated. The growth rate was correlated to the effective stress intensity factor, and the relation was found to be approximated by a power law equation. The fatigue crack growth property obtained as above was applied to an estimation of fatigue life of specimens without artificial flaws. The flaw size effect was also discussed based on the result,

Picolinic acid-based metallic chelators, e.g., neunpa and octapa, have attracted much attention as promising scaffolds for radiotheranostic agents, particularly those containing larger α-emitting radiometals. Furthermore, albumin binder (ALB) moieties, which noncovalently bind to albumin, have been utilized to improve the pharmacokinetics of radioligands targeting various biomolecules. In this study, we designed and synthesized novel neunpa and octapa derivatives (Neunpa-2 and Octapa-2, respectively), which contained a prostate-specific membrane antigen (PSMA)-binding moiety (model targeting vector) and an ALB moiety. We evaluated the fundamental properties of these derivatives as radiotheranostic agents using 111In. In a cell-binding assay using LNCaP (PSMA-positive) cells, [111In]­In-Neunpa-2 and [111In]­In-Octapa-2 specifically bound to the LNCaP cells. In addition, a human serum albumin (HSA)-binding assay revealed that [111In]­In-Neunpa-2 and [111In]­In-Octapa-2 exhibited greater binding to HSA than their non-ALB-conjugated counterparts ([111In]­In-Neunpa-1 and [111In]­In-Octapa-1, respectively). A biodistribution assay conducted in LNCaP tumor-bearing mice showed that the introduction of the ALB moiety into the 111In-labeled neunpa and octapa derivatives resulted in markedly enhanced tumor uptake and retention of the radioligands. Furthermore, single-photon emission computed tomography imaging of LNCaP tumor-bearing mice with [111In]­In-Octapa-2 produced tumor images. These results indicate that [111In]­In-Octapa-2 may be a useful PSMA imaging probe and that picolinic acid-based ALB-conjugated radiometallic complexes may be promising candidates as radiotheranostic agents.

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Insulinomas are neuroendocrine tumors that are derived from pancreatic β-cells, and they often overexpress the glucagon-like peptide-1 receptor (GLP-1R). Radiolabeled exendin-4 derivatives have been used to noninvasively detect the GLP-1R during the diagnosis and preoperative localization of insulinomas; however, their marked renal accumulation can hinder the imaging of pancreatic tail lesions. In this study, we designed and synthesized 111In-labeled exendin-4 derivatives that possessed 4-(4-substituted phenyl)-moieties as albumin binder (ALB) moieties ([111In]­In-E4DA2–4), and studied their structure–activity relationships and pharmacokinetics (as well as those of [111In]­In-E4DA1, which we previously reported) to determine their usefulness as radioligands for GLP-1R imaging. 111In-labeling was performed by reacting maleimide precursors with [111In]­InCl3 in 2-(N-morpholino)­ethanesulfonic acid buffer, and then, the products were conjugated with exendin-4-Cys40. A saturation binding assay using GLP-1R-expressing INS-1 cells was carried out to evaluate the in vitro affinity of the radioligands for the cells. In addition, the affinity of the 111In-labeled derivatives for human serum albumin (HSA) was evaluated in an HSA-binding assay. Furthermore, an in vivo biodistribution study and single-photon emission computed tomography (SPECT) imaging were performed using INS-1 tumor-bearing mice. [111In]­In-E4DA1–4 were prepared at radiochemical yields of 6–17%. In the saturation binding assay, [111In]­In-E4DA1–4 showed a similar affinity for the INS-1 cells, indicating that the kind of ALB moiety used had no effect on the affinity of the exendin-4 derivatives for the cells. In the HSA-binding assay, [111In]­In-E4DA1–4 all bound to HSA. In the biodistribution assay, [111In]­In-E4DA1–4 exhibited marked tumor accumulation and retention. In addition, they showed lower renal accumulation than previously reported exendin-4-based radioligands without ALB moieties. The pharmacokinetics of the 111In-labeled exendin-4 derivatives varied markedly according to the kind of ALB moiety used. In particular, [111In]­In-E4DA2, which contained a 4-(4-bromophenyl)­butyric acid derivative as an ALB moiety, showed the highest tumor accumulation. SPECT imaging with [111In]­In-E4DA2 clearly visualized INS-1 tumors with no marked accumulation in normal organs. These results provide important information that will aid the design of novel exendin-4-based radioligands targeting the GLP-1R.