Archives
IC is a rat mAb
IC2 is a rat mAb specifically binding to insulin granula [127,128]. Although this mAb was discovered 30 years ago, it has only recently been used for β-cell imaging in vivo. Moore et al. used this mAb for β-cell imaging in 2001 [129]. After DTPA conjugation, IC2 was labeled with 111In. Both in vitro and in vivo studies demonstrated the specific targeting of 111In-DTPA-IC2 to β-cell surface structures. The authors further found that the uptake of 125I-labeled IC2 directly correlated with BCM in diabetic and normal animals [129]. However, in addition to the slow blood clearance of this probe due to its large size, no experimental or clinical studies verify the application of this mAb in human diagnostics.
Alternatively, single-chain scopolamine hydrobromide other antibody fragments may show high pancreas uptake and fast blood clearance. For example, Ueberberg and colleagues screened a single-chain antibody library and reported that 125I-labeled single-chain antibodies successfully monitored BCM in rats [130]. Eriksson et al. radiolabeled a novel Zinc transporter 8 (ZnT8)-targeting antibody fragment, Ab31, using 125I and reported that the binding affinity of this probe to insulinomas and the pancreatic accumulation of this tracer was higher than that of 125I-labeled exendin-4 [131]. These initial results indicate that antibody fragments and single-chain antibodies may be promising alternatives for β-cell imaging, since they have similar specificities and affinities toward their corresponding targets with faster clearance because of their much smaller sizes [132].
Imaging agents for other emerging targets
Optical imaging probes
Imaging transplanted islets
Imaging insulinomas and β-cell hyperplasia
One of the most promising and useful clinical applications of noninvasive β-cell imaging lies in the visualization of insulinomas and β-cell hyperplasia [213,214]. Insulinoma, the most common cause of hypoglycemia in adult patients not diagnosed with diabetes, occurs in 1–4 cases per million of the general population and accounts for 1%–2% of all pancreatic malignancies [215,216]. Several radiotracers, including 18F-FDOPA [[217], [218], [219], [220]], 11C-5-hydroxytryptophan (11C-5-HTP) [221], and various imaging probes derived from exendin analogs [222,223], have been successfully used to detect insulinomas. Sweet et al. initially screened and identified several candidate molecules including L-DOPA as potential β-cell imaging agents [224]. Although several studies have shown that the relatively low in vitro binding specificity of l-DOPA to β-cells did not qualify this small molecule for further development as a PET imaging tracer to assess BCM, 18F-FDOPA could be used to noninvasively assess hyperinsulinism [27,[225], [226], [227], [228]]. In addition to its role in detecting BCM and transplanted islets [[229], [230], [231]], 11C-5-HTP can also be used to detect neuroendocrine tumors due to high intracellular uptake of 5-HTP [232]. However, to increase tumor uptake and lower physiological pancreatic uptake, patient premedication with carbidopa is generally needed for 18F-FDOPA and 11C-5-HTP PET imaging [233,234]. Furthermore, the dosage and the optimal protocol for carbidopa premedication are not definitively standardized in clinical practice [220].
While benign insulinomas express the GLP-1R at a high density and somatostatin receptors (SSTRs) in low levels, 73% of malignant insulinomas have high expression levels of SSTRs, with the remaining malignant insulinomas overexpressing GLP-1R [235,236]. In order to enhance the circulation and overcome the rapid degradation of GLP-1 in vivo by enzymes, a series of conformationally-constrained GLP-1 analogs have been developed [237]. One such example is EM3106B, which has an unnatural α-aminoisobutyric acid and multiple lactam bridges and has been labeled with 18F-FBEM [238]. Due to the challenge in synthesizing derivatives of EM3106B, Kiesewetter and colleagues modified exendin-4 with a cysteine to allow site-specific labeling with 18F-FBEM or aluminum 18F-fluoride [239,240]. Based on these encouraging preclinical results, initial clinical attempts found that 68Ga-labeled exendin-4 identified both occult and metastatic insulinomas [[241], [242], [243]]. A recent comparative study showed 68Ga-NOTA-exendin-4 identified 42 out of 43 histopathologically-proven insulinomas (Fig. 5), superior to 99mTc-HYNIC-TOC SPECT/CT or other traditional imaging modalities [28]. The advantageous diagnostic value of PET over SPECT may result from improvements in partial-volume effects and superior spatial resolution, as was demonstrated by a recent study which compared the detection efficacies of 68Ga-DOTA-exendin-4 PET/CT and 111In-DOTA-exendin-4 SPECT/CT in patients with hidden insulinomas [243]. One of the critical factors in the realization of routine clinical examinations with an agent is the accessibility of the radiopharmaceutical. Considering that [68Ga]Ga-DO3A-VSCys40-exendin-4 successfully localized multiple small liver and lymph node metastases from insulinomas and the fact that the tracer was prepared manually [241], Velikyan et al. further established automated production and quality control methods for preparing [68Ga]Ga-DO3A-VSCys40-exendin-4 [244]. These efforts will certainly pave the way for broader clinical use of these tracers in the early and precise diagnosis of insulinomas.