PET Imaging of Angiogenesis

Abstract

Angiogenesis is a highly-controlled process that is dependent on the intricate balance of both promoting and inhibiting factors, involved in various physiological and pathological processes. A comprehensive understanding of the molecular mechanisms that regulate angiogenesis has resulted in the design of new and more effective therapeutic strategies. Due to insufficient sensitivity to detect therapeutic effects by using standard clinical endpoints or by looking for physiological improvement, a multitude of imaging techniques have been developed to assess tissue vasculature on the structural, functional and molecular level. Imaging is expected to provide a novel approach to noninvasively monitor angiogenesis, to optimize the dose of new antiangiogenic agents and to assess the efficacy of therapies directed at modulation of the angiogenic process. All these methods have been successfully used preclinically and will hopefully aid in antiangiogenic drug development in animal studies. In this review article, the application of PET in angiogenesis imaging at both functional and molecular level will be discussed. For PET imaging of angiogenesis related molecular markers, we emphasize integrin alpha(v)beta(3), VEGF/VEGFR, and MMPs.

Figure 1

¹⁸F-Galacto-RGD scans of 2 patients with metastases from malignant melanoma and different tracer uptake. (Upper row images) An 89-y-old female patient with metastasis in subcutaneous fat in gluteal area on left side (arrow with dotted line). Tumor can be clearly delineated in CT scan (A), whereas it shows no significant uptake in ¹⁸F-Galacto-RGD PET scan (B; 60 min after injection). (Lower row images) A 36-y-old female patient with lymph node metastasis in right groin (arrow). Again, tumor is clearly visualized in CT scan (C) but also shows intense tracer uptake in ¹⁸F-Galacto-RGD PET scan (D; 89 min after injection; SUV, 6.8). Reproduced from Beer et al. with permission.

Figure 2

(A) Decay-corrected whole-body coronal microPET images of athymic female nude mice bearing U87MG tumor at 5, 15, 30, 60, 120, and 180 min after injection of ¹⁸F-FPRGD4 (3.7 MBq [100 μCi]). (B) Decay-corrected whole-body coronal microPET images of c-neu oncomice at 30, 60, and 150min (5-min static image) after intravenous injection of ¹⁸F-FPRGD4. (C) Decay-corrected whole-body coronal microPET images of orthotopic MDA-MB-435 tumor-bearing mouse at 30, 60, and 150 min after intravenous injection of ¹⁸F-FPRGD4. (D) Decay-corrected whole-body coronal microPET images of DU-145 tumor-bearing mouse (5-min static image) after intravenous injection of ¹⁸F-FPRGD4. (E) Coronal microPET images of a U87MG tumor-bearing mouse at 30 and 60 min after coinjection of ¹⁸F-FPRGD4 and a blocking dose of c(RGDyK). Arrows indicate tumors in all cases. Reproduced from Wu et al. with permission.

FIGURE 3

(A) Coronal CT image and fusion of microPET and CT images (168 h after injection) enables adequate quantitative measurement of ⁸⁹Zr-bevacizumab in the tumor; (B) Coronal planes of microPET images after injection of ⁸⁹Zr-bevacizumab. Reproduced from Nagengast et al. with permission.

Figure 4

MicroPET of ⁶⁴Cu-DOTA-VEGF₁₂₁ in U87MG tumor-bearing mice. (A) Serial microPET scans of large and small U87MG tumor-bearing mice injected intravenously with 5–10 MBq of ⁶⁴Cu-DOTA-VEGF₁₂₁. Mice injected with ⁶⁴Cu-DOTA-VEGF₁₂₁ 30 min after injection of 100 μg VEGF₁₂₁ are also shown (denoted as “Small tumor + block”). (B) Two-dimensional whole-body projection of the 3 mice shown in A at 16 h after injection of ⁶⁴Cu-DOTA-VEGF₁₂₁. Tumors are indicated by arrows. Reproduced from Cai et al. with permission.