Positron emission tomography tracers for imaging angiogenesis

Abstract

Position emission tomography imaging of angiogenesis may provide non-invasive insights into the corresponding molecular processes and may be applied for individualized treatment planning of antiangiogenic therapies. At the moment, most strategies are focusing on the development of radiolabelled proteins and antibody formats targeting VEGF and its receptor or the ED-B domain of a fibronectin isoform as well as radiolabelled matrix metalloproteinase inhibitors or alpha(v)beta(3) integrin antagonists. Great efforts are being made to develop suitable tracers for different target structures. All of the major strategies focusing on the development of radiolabelled compounds for use with positron emission tomography are summarized in this review. However, because the most intensive work is concentrated on the development of radiolabelled RGD peptides for imaging alpha(v)beta(3) expression, which has successfully made its way from bench to bedside, these developments are especially emphasized.

Fig. 1

Serial microPET imaging 1, 4 and 20 h p.i. of tumour-bearing mice injected intravenously with ⁶⁴Cu-DOTA-VEGF₁₂₁ or ⁶⁴Cu-DOTA-VEGF_DEE, respectively. Coronal slices containing the tumours (arrowheads) are shown. The study showed that ⁶⁴Cu-DOTA-VEGF_DEE had significantly lower kidney uptake than ⁶⁴Cu-DOTA-VEGF₁₂₁ while the tumour and other major organ uptake of both tracers was comparable (reproduced with permission [30])

Fig. 2

Small animal PET images of a tumour-bearing nude mouse injected with the anti ED-B domain antibody format [¹²⁴I]L19-SIP. Coronal images 24 h (a) and 48 h (b) after tracer injection showed clearly visible tumours on both flanks of the mouse. At 24 h p.i. high uptake was also found in the stomach (may be due to some deiodination) and to a lesser extent in the bladder which disappeared at 48 h p.i. (reproduced with permission [53])

Fig. 3

Planar scintigraphy imaging of tumour-bearing mice injected with 2-(4-[¹²³I]Iodo-biphenyl-4-sulfonylamino)-3-(1H-indol-3-yl)-propionic acid at 6, 24 and 48 h p.i. demonstrated low tracer uptake in the tumour (indicated by arrows) (reproduced with permission [77])

Fig. 4

Correlation of tracer accumulation and α_vβ₃ expression. a–c Patient with a soft tissue sarcoma dorsal of the right knee joint. a The sagittal section of a [¹⁸F]Galacto-RGD PET acquired 170 min p.i. showed circular peripheral tracer uptake in the tumour with variable intensity and a maximum SUV at the apical-dorsal aspect of the tumour (arrow). b The image fusion of the [¹⁸F] Galacto-RGD PET and the corresponding CT scan showed that the regions of intense tracer uptake correspond with the enhancing tumour wall, whereas the non-enhancing hypodense centre of the tumour showed no tracer uptake. c Immunohistochemistry of a peripheral tumour section using an anti-α_vβ₃ monoclonal antibody demonstrated intense staining predominantly of tumour vasculature. d–f Patient with malignant melanoma and a lymph node metastasis in the right axilla. d The axial section of a [¹⁸F] Galacto-RGD PET acquired 140 min p.i. shows intense focal uptake in the lymph node (arrow). e Image fusion of the [¹⁸F]Galacto-RGD PET and the corresponding CT scan. f Immunohistochemistry of the lymph node using the anti-α_vβ₃ monoclonal antibody demonstrated intense staining predominantly of tumour cells and also blood vessels (reproduced with permission [105])

Fig. 5

Comparison of small animal PET images of tumour-bearing mice. First row Coronal images 20, 60 and 120 min after injection of ¹⁸F-Galacto-RGD. Second and third rows Coronal images 20, 60 and 120 min after injection of ¹⁸F-FP-PRGD2 and ¹⁸F-FP-SRGD2, respectively. For all tracers best tumour to background ratios are found after 120 min p.i. However, due to higher absolute uptake the dimeric RGD peptides showed superior imaging quality in this animal model (reproduced with permission [113])

Fig. 6

¹⁸F-AH111585 PET and corresponding CT showed increased signal intensity in the periphery of lesions in patients with lung and pleural metastases (a). Intralesion heterogeneity of tracer uptake within the pleural metastasis is found in the PET image, which was identified as non-necrotic by the CT section (b). Liver metastasis was imaged as hypointense lesion because of high background signal (c). High tracer uptake in spleen is possibly due to blood pooling (reproduced with permission [131])

Fig. 7

Example of multiparametric multimodality MRI and PET imaging in a patient with lung cancer in the left upper lobe (arrows). In the upper row in the images before start of chemotherapy, FDG PET/CT shows the intense glucose metabolism of the tumour, and [¹⁸F]Galacto-RGD PET/MRI image fusion shows intense α_vβ₃ expression of the tumour. Functional imaging by MRI shows restricted water diffusion in the ADC map of the diffusion-weighted MRI (“apparent diffusion coefficient”) as an indicator of high cellularity and elevated tissue perfusion in the parametric map of K^trans from DCE MRI. Two weeks after start of chemotherapy, glucose metabolism shows no substantial change, ADC has slightly increased (about 10%) and [¹⁸F]Galacto-RGD uptake has decreased by 20%. K^trans has decreased especially in the central parts of the tumour. This demonstrates that changes of functional and molecular parameters of angiogenesis and tumour biology can be measured early after onset of chemotherapy by combined MRI and PET, which might be helpful for response assessment in the future (unpublished data from A. Beer)