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    • Notably Cu labeled dimeric exendin subunit which was

    2022-01-17

    Notably, 64Cu-labeled dimeric exendin-4 subunit, which was designated as 64Cu-Mal2Sar-(exendin-4)2, showed higher tumor uptake than that of the monomeric exendin-4 subunit [245]. Besides the most commonly-used GLP-1R agonists exendin-3 and -4 and their derivatives, exendin (9-39) exhibits strong binding affinity for GLP-1R but is less likely to cause hypoglycemia [246,247]. As a result, radiolabeled derivatives of this peptide have also been investigated in the context of insulinoma. Kimura et al. reported that 111In-BnDTPA-exendin (9-39) clearly depicted tumors at 30 min post-injection in INS-1 tumor-bearing mice [248]. Theoretically, dual-targeting of GLP1-R and SSTR could thus localize all insulinomas. To this purpose, a hybrid peptide targeting both GLP-1R and SSTR has also been prepared and evaluated after labeling using 99mTc, and the preliminary results from Medina-García et al. showed that the probe is successful in identifying GRP-1R- and SSTR- double positive tumors or tumors with either GRP-1R or SSTR expression [249,250].
    Conclusions and future perspectives Currently, ITD 1 receptor is usually diagnosed by blood tests that measure glucose tolerance or abnormal glycosylation of hemoglobin (termed HbA1c) [5, 251]. Ideally, diabetes should be diagnosed at a very early stage when the BCM and β-cell function have just changed. As the relatively small β-cell islets are scattered throughout the pancreas and constitute a minor part of the pancreas, and a highly β-cell-specific ligand for labeling is currently not available, imaging them is still very challenging [16,106,252]. Possible imaging techniques require several properties, such as high sensitivity, high spatial resolution, and low cost, which limit the feasible choices. Although the path leading from encouraging preclinical outcomes to bedside applications is not always easy, great efforts and long-term investments have been devoted to improve the diagnostic accuracy of diabetes/BCM in the laboratory using highly β-cell-specific molecular imaging probes [253]. Of the probes discussed above, GLP1-based imaging probes [28,101,107,118,179,254,255], manganese-based probes [34,45], and zinc-based probes [140], and several other probes emerge as the most promising candidates for β-cell imaging (Table 1). Clinical translation of selected probes will facilitate early diagnosis of patients with diabetes and therefore timely intervention. Considering the fact that β-cells comprise only a small proportion of the total pancreatic mass and substantial variation in BCM exists between different individuals, the major value of β-cell imaging may lie in longitudinal studies where imaging results of two or more time points will indicate the dynamic changes of BCM in the same individual over time. In addition, noninvasive β-cell imaging methods will enable assessment of survival of transplanted islets [256], and precise detection of insulinomas [214]. For future development, there are several aspects that we may take into consideration when developing β-cell-specific probes. First, since tracers nonspecific for β-cells may lead to an overestimation of the BCM, future efforts should be devoted to discovering tracers of high sensitivity and specificity for β-cells. Hopefully, the most optimal candidates can be obtained by genome-wide loss-of-function screening and screening of the concomitant epigenetic, proteomic and metabolomic libraries [130,[257], [258], [259]]. For example, a recent study using proteomic screening methods identified G coupled protein GPR44 as a surrogate marker for β-cells [260], and follow-up studies reported that radiolabeled GPR44 ligands, [3H]AZD 3825 [261], and [11C]AZ12204657 [262], could be used to visualize β-cells in vivo. Interdisciplinary research and collaboration from the fields of chemistry, biology, radiology, and pharmacy will also allow great strides toward developing β-cell specific probes. Secondly, longitudinal quantification and measurement are necessary to track the dynamic changes of BCM over time, especially for transplanted islets. This means that the tracer applied for imaging has to be non-toxic without damaging β-cells or other tissue. For this reason, radiomanganese PET/CT imaging, rather than other Mn2+-based agents, seems to be a feasible method to assess BCM, since it uses far less tracer [45]. Radiolabeled exendin analogs can also be alternative options, as dosimetry studies showed that those probes had acceptable radiation-induced damage to islets in rats and humans [263]. While reporter gene-based β-cell imaging approaches showed great promise for monitoring islet transplantation [176,177], these methods rely on the ex vivo transfection of β-cells. Therefore, whether the manipulation and expression of foreign proteins will trigger immune responses or malignant transformation of the transfected cells needs to be addressed [264,265].