PET with FDG is frequently used for oncological application to assess tissue viability. However, owing to the low FDG uptake in some tumor types, like in the neuroendocrine carcinomas, there is a need for new radiotracers. One idea is to study the expression of different receptors in order to guide diagnostics and even more therapy in that direction, e.g. using a radionuclide-based therapy. NETs originate mostly from the gastroenteropancreatic tract and express specific receptors like amine and peptide receptors (somatostatin, vasointestinal peptide receptors, bombesin, cholecystokinin, gastrin and/or substance P) . Adams et al. reported the comparison of different tracers in detecting malignant NETs and revealed that increased FDG uptake was associated with malignancy . In nude mice bearing the AR4-2J tumor, tumor uptake of both 90Y and 111In-DOTATOC 4 h after injection was five times higher than with 111In-DTPA-octreotide . We had reported on 68Ga-DOTATOC studies in patients with NETs and an enhanced uptake in metastases of NETs . Furthermore, we have shown that the global DOTATOC uptake in NETs is mainly dependent on k 1 (receptor binding) and VB (fractional blood volume) and less on the k 3 (internalization). 68Ga-DOTATOC was better suited than 18F-FDG for the diagnosis of metastatic NETs. The 68Ga-DOTATOC uptake was also used as a parameter for a radionuclide therapy with 90Y-DOTATOC. Patients with lesions demonstrating an enhanced 68Ga-DOTATOC uptake (> 5.0 SUV) were selected for radionuclide therapy .
Bombesin and the two mammalian bombesin-like peptides, BB1 and BB2 regulate many biologic response processes through activation of distinct receptor subtypes, including modulation of smooth muscle contraction, secretion of neuropeptides and hormones, as well as stimulation of cell growth [38, 39]. Activation of neuromedin B (BB1) receptors has been reported in various human cancers . Experimental studies demonstrated an enhanced bombesin receptor expression in several human adult glioblastoma cell lines as well as in two pediatric human glioblastoma cell lines . We reported on an enhanced 68Ga-BZH3 uptake in a subgroup of patients with gastrointestinal stromal tumors , and quantitative 68Ga-BZH3 studies were helpful in patients with recurrent gliomas for tumor grading and the differentiation between high- and low-grade tumors . In addition, other bombesin analogues 64Cu-, 99mTc-, 188Re-, 177Lu-, 90Y-, and 111In have been reported to be promising radiotracers for PET imaging of many human cancers overexpressing the GRP receptor such as breast cancer and prostate carcinoma [6–13, 40, 41].
Integrins play a key role in angiogenesis and tumor metastasis by mediating tumor cell invasion and movement across blood vessel, whereas integrins expressed on endothelial cells modulate cell migration and survival during the angiogenic cascade. A common feature of many integrins like ανβ3 is that they bind to extracellular matrix proteins via the three amino acid sequence arginine-glycine-aspartic acid (RGD) [42, 43]. Radiolabeled RGD-peptides, the integrin ανβ3-specific tracers, have been developed for PET and SPECT imaging. A mass of data suggested that ανβ3 expression can be quantified by radiolabeled RGD-peptides [44–46]. In this study, 68Ga-BZH3 and 68Ga-RGD4 were used as tracers for PET to assess the receptor expression in AR42J tumor-bearing nude rats by comparison.
Quantitative dynamic PET provides the possibility for absolute tracer quantification and is superior to static images, which are widely used, but do not provide information on tracer kinetics. Furthermore, the use of a two-compartment model is the superior approach for the assessment of tracer kinetics, and is accepted for research purposes . Concerning the 68Ga-BZH3 kinetics, k 1 is a parameter that reflects the receptor binding and k 3 is a parameter that reflects the internalization of the tracer. A lower receptor binding of 68Ga-BZH3 was reported in gliomas as compared with 68Ga-DOTATOC in meningiomas, but higher internalization, were proved . In the present study, the comparison of the 68Ga-BZH3 kinetics with the 68Ga-RGD4 kinetics in the ARJ 42 tumor-bearing nude rats revealed higher mean values of k 1 for 68Ga-BZH3 (median, 0.3506) as compared with 68Ga-RGD4 (median 0.2728), and comparable k 3 values (median, 0.1177 vs. 0.1180). According to these data, the tracers' accumulation in this neuroendocrine tumor cell line is primarily depends on the receptor binding and less on the internalization.
Generally, 68Ga-BZH3 uptake was lower than 18F-FDG . Herein, we found 68Ga-BZH3 uptake was higher than that of 68Ga-RGD4, and the values were relatively comparable in comparison to that reported in gliomas . In particular, there were significant differences between VB, K 1, k 4, RBP, and FD. The fractional blood values VB of 68Ga-BZH3 were higher than that of 68Ga-RGD4 (median, 0.0903 vs. 0.0574), however for both tracers they are low in comparison to those reported for other tracers, like 68Ga-DOTATOC and 18F-FDG. This is in accordance to previous published data, e.g. in melanoma patients and confirm the hypothesis that the absolute value of VB depend on the applied tracer . The VB and RBP values for 68Ga-BZH3 were more spread out than those determined for 68Ga-RGD4. A possible explanation is that the tracer uptake of 68Ga-RGD4 was generally lower than that of 68Ga-BZH3.
Cancer is often characterized by chaotic, poorly regulated growth. Recent studies have shown that fractal geometry can be useful to describe the pathological architecture of tumors and angiogenesis. Fractals can be useful measures of pathologies of the vascular architecture, the tumor border, and the cellular morphology . The FD is used to characterize the chaotic nature of the tracer's distribution in primary tumors and metastases, based on the box counting procedure of chaos theory, for the analysis of dynamic PET data. In the present study, FD values for 68Ga-BZH3 were ranged from 1.066 to 1.150 (median, 1.142), higher than that for 68Ga-RGD4 (median, 0.989), but both are lower compared with those measured in malignancies with different tracers, such as 68Ga-DOTATOC, 18F-FDG, 15O-water, and 18F-DOPA (a median FD exceed 1.25) [48, 50].