Assessment of alphavbeta3 integrin expression after myocardial infarction by positron emission tomography.

AIMS: The purpose of this study was to determine the feasibility of a new positron emission tomography (PET) imaging approach using an (18)F-labelled alpha(v)beta(3) integrin antagonist ((18)F-Galacto-RGD) to monitor the integrin expression after myocardial infarction. METHODS AND RESULTS: Male Wister rats were subjected to 20 min transient left coronary artery occlusion followed by reperfusion. Autoradiographic analysis and in vivo PET imaging were used to determine myocardial (18)F-Galacto-RGD uptake at different time points following reperfusion. RESULTS: PET imaging and autoradiography demonstrated no significant focal myocardial (18)F-Galacto-RGD uptake in non-operated control rats and at day 1 after reperfusion. However, focal accumulation in the infarct area started at day 3 (uptake ratio = 1.91 +/- 0.22 vs. remote myocardium), peaked between 1 (3.43 +/- 0.57) and 3 weeks (3.43 +/- 0.95), and decreased to 1.96 +/- 0.40 at 6 months after reperfusion. Pretreatment with alpha(v)beta(3) integrin antagonist c(-RGDfV-) significantly decreased tracer uptake, indicating the specificity of tracer uptake. The time course of focal tracer uptake paralleled vascular density as measured by CD31 immunohistochemical analysis. CONCLUSION: Regional (18)F-Galacto-RGD accumulation suggests up-regulation of alpha(v)beta(3) integrin expression after myocardial infarction, which peaks between 1 and 3 weeks and remains detectable until 6 months after reperfusion. This new PET tracer is promising for the monitoring of myocardial repair processes.

Comparison of integrin alphaVbeta3 expression and glucose metabolism in primary and metastatic lesions in cancer patients: a PET study using 18F-galacto-RGD and 18F-FDG.

UNLABELLED: The expression of alpha(v)beta(3) and glucose metabolism are upregulated in many malignant lesions, and both are known to correlate with an aggressive phenotype. We evaluated whether assessment of alpha(v)beta(3) expression and of glucose metabolism with PET using (18)F-galacto-RGD and (18)F-FDG provides complementary information in cancer patients. METHODS: Eighteen patients with primary or metastatic cancer (non-small cell lung cancer [NSCLC], n = 10; renal cell carcinoma, n = 2; rectal cancer, n = 2; others, n = 4) were examined with PET using (18)F-galacto-RGD and (18)F-FDG. Standardized uptake values (SUVs) were derived by volume-of-interest analysis. (18)F-Galacto-RGD and (18)F-FDG PET results were compared using linear regression analysis for all lesions (n = 59; NSCLC, n = 39) and for primaries (n = 14) and metastases to bone (n = 11), liver (n = 10), and other organs (n = 24) separately. RESULTS: The sensitivity of (18)F-galacto-RGD PET compared with clinical staging was 76%. SUVs for (18)F-FDG ranged from 1.3 to 23.2 (mean +/- SD, 7.6 +/- 4.9) and were significantly higher than SUVs for (18)F-galacto-RGD (range, 0.3-6.8; mean +/- SD, 2.7 +/- 1.5; P < 0.001). There was no significant correlation between the SUVs for (18)F-FDG and (18)F-galacto-RGD for all lesions (r = 0.157; P = 0.235) or for primaries, osseous or soft-tissue metastases separately (P > 0.05). For the subgroup of lesions in NSCLC, there was a weak correlation between (18)F-FDG and (18)F-galacto-RGD uptake (r = 0.353; P = 0.028). CONCLUSION: Tracer uptake of (18)F-galacto-RGD and (18)F-FDG does not correlate closely in malignant lesions. Whereas (18)F-FDG PET is more sensitive for tumor staging, (18)F-galacto-RGD PET warrants further evaluation for planning and response evaluation of targeted molecular therapies with antiangiogenic or alpha(v)beta(3)-targeted drugs.

Patterns of alphavbeta3 expression in primary and metastatic human breast cancer as shown by 18F-Galacto-RGD PET.

UNLABELLED: The integrin alpha(v)beta(3) is a key player in angiogenesis and metastasis. Our aim was to study the uptake patterns of the alpha(v)beta(3)-selective PET tracer (18)F-galacto-RGD in invasive ductal breast cancer. METHODS: Sixteen patients with primary (n = 12) or metastasized breast cancer (n = 4) were examined with (18)F-galacto-RGD PET. Standardized uptake values (SUVs) were derived by region-of-interest analysis, and immunohistochemistry of alpha(v)beta(3) expression was performed (n = 5). RESULTS: (18)F-Galacto-RGD PET identified all invasive carcinomas, with SUVs from 1.4 to 8.7 (mean +/- SD, 3.6 +/- 1.8; tumor-to-blood and tumor-to-muscle ratios, 2.7 +/- 1.6 and 6.2 +/- 2.2, respectively). Lymph-node metastases were detected in 3 of 8 patients (mean SUV, 3.3 +/- 0.8). SUVs in distant metastases were heterogeneous (2.9 +/- 1.4). Immunohistochemistry confirmed alpha(v)beta(3) expression predominantly on microvessels (5/5) and, to a lesser extent, on tumor cells (3/5). CONCLUSION: Our results suggest generally elevated and highly variable alpha(v)beta(3) expression in human breast cancer lesions. Consequently, further imaging studies with (18)F-galacto-RGD PET in breast cancer patients for assessment of angiogenesis or planning of alpha(v)beta(3)-targeted therapies are promising.

[18F]galacto-RGD positron emission tomography for imaging of alphavbeta3 expression on the neovasculature in patients with squamous cell carcinoma of the head and neck.

PURPOSE: [(18)F]Galacto-RGD has been developed for positron emission tomography (PET)-imaging of alphavbeta3 expression, a receptor involved in angiogenesis and metastasis. Our aim was to study the feasibility of PET imaging with [(18)F]Galacto-RGD in patients with squamous cell carcinoma of the head and neck (SCCHN). EXPERIMENTAL DESIGN: Eleven patients with primary diagnosis of SCCHN were examined. After injection of 140 to 200 MBq [(18)F]Galacto-RGD, static emission scans 60 min post injection from the head to the abdomen (n = 11) and dynamic scans >60 min covering the tumor region (n = 6) for kinetic modeling were acquired. Standardized uptake values (SUV) were measured in tumors, muscle and oral mucosa. Immunohistochemistry was done using an alphavbeta3-specific antibody (n = 7). Image fusion with magnetic resonance imaging and/or computed tomography (CT) scans (n = 8) and calculation of tumor subvolumes based on SUVs was done using the iPlan software (BrainLAB). RESULTS: [(18)F]Galacto-RGD PET identified 10 of 12 tumors, with SUVs ranging from 2.2 to 5.8 (mean, 3.4 +/- 1.2). Two tumors <5 mm were missed. Tumor/blood and tumor/muscle ratios were 2.8 +/- 1.1 and 5.5 +/- 1.6, respectively. Tumor kinetics was consistent with a two-tissue compartmental model with reversible specific binding. Immunohistochemistry confirmed alphavbeta3 expression in all tumors with alphavbeta3 being located on the microvessels in all specimens and additionally on tumor cells in one specimen. Image fusion of [(18)F]Galacto-RGD PET with magnetic resonance imaging/multislice CT and definition of tumor subvolumes was feasible in all cases. CONCLUSIONS: [(18)F]Galacto-RGD PET allows for specific imaging of alphavbeta3 expression in SCCHN with good contrast. Image fusion and definition of tumor subvolumes is feasible. This technique might be used for the assessment of angiogenesis and for planning and response evaluation of alphavbeta3-targeted therapies.

Non-invasive assessment of inter-and intrapatient variability of integrin expression in metastasized prostate cancer by PET.

PURPOSE: Due to the high expression of the integrin αvß3 not only on endothelial cells, but also on mature osteoclasts and prostate cancer cells, imaging of osseous metastases with αvß3-targeted tracers seems promising. However, little is known about the patterns of αvß3-expression in metastasized prostate cancer lesions in-vivo. Thus we evaluated the uptake of the αvß3-specific PET tracer [18F]Galacto-RGD for assessment of bone metastases in prostate cancer patients. RESULTS: [18F]Galacto-RGD PET identified 58/74 bone-lesions (detection rate of 78.4%) and lymph node metastases in 2/5 patients. The SUVmean was 2.12+/-0.94 (range 0.70-4.38; tumor/blood 1.36+/-0.53; tumor/muscle 2.82+/-1.31) in bone-lesions and 2.21+/-1.18 (range 0.75-3.56) in lymph node metastases. Good visualization and detection of bone metastases was feasible due to a low background activity of the surrounding normal bone tissue. METHODS: 12 patients with known metastasized prostate cancer according to conventional staging (including bone-scintigraphy and contrast-enhanced CT; median PSA 68.63 ng/ml, range 3.72-1935) were examined with PET after i.v.-injection of [18F]Galacto-RGD. Two blinded nuclear-medicine physicians evaluated the PET-scans in consensus concerning lesion detectability. Volumes-of-interest were drawn in the PET-scans over all metastases defined by conventional staging (maximum of 11 lesions/patient), over the left ventricle, liver and muscle and standardized-uptake-values (SUVs) were calculated. CONCLUSIONS: Our data show generally elevated uptake of [18F]Galacto-RGD in bone metastases from prostate cancer with a marked inter- and intrapatient variability. While [18F]Galacto-RGD PET is inferior to bone scintigraphy for detection of osseous metastases, it might be valuable in patient screening and monitoring of αvß3-targeted therapies due to the high variability of αvß3-expression.

Evaluation of cardiac beta-adrenoreceptors in the isolated perfused rat heart using (S)-11C-CGP12388.

UNLABELLED: (S)-(11)C-CGP12388 ((11)C-CGP12388) was recently developed as an in vivo PET tracer for the evaluation of cardiac beta-adrenergic receptors. The purpose of this study was to evaluate the myocardial kinetics of (11)C-CGP12388 using the perfused rat heart model. METHODS: Normal rat hearts were cannulated for retrograde perfusion according to the Langendorff method. Studies were performed using constant coronary flow rates of 12 mL/min (high flow: n = 6) and 6 mL/min (low flow: n = 6). Beta-adrenergic-blocking studies were also done using propranolol (blocking: n = 6). Two bolus injections of (11)C-CGP12388 were administered at a 25-min interval, and time-activity curves were measured using bismuth germanate detectors. The beta-adrenergic receptor density (B(max)) and total distribution volume (DV(tot)) were estimated using compartmental modeling. After the experiment, B(max) in vitro was measured for all hearts using (3)H-CGP12177, and the values were compared with the B(max) estimated in isolated hearts. RESULTS: DV(tot) was significantly lower in the blocking group than in the high-flow group (P < 0.01), and there was no significant difference in DV(tot) between the high- and the low-flow groups. B(max) values estimated from (11)C-CGP12388 kinetics were 5.05 +/- 0.90 pmol/g under the high-flow model and 5.20 +/- 0.63 pmol/g under the low-flow model. The B(max) results in isolated hearts correlated significantly with the measured in vitro B(max) values (r(2) = 0.69; P < 0.001). CONCLUSION: Beta-adrenoreceptor density in the isolated rat heart can be quantified using (11)C-CGP12388 and a 2-injection protocol. The binding of the tracer was flow independent, with low nonspecific binding. These results suggest that (11)C-CGP12388 is a promising PET tracer that may be applicable to human studies.

18F-labeled galacto and PEGylated RGD dimers for PET imaging of αvß3 integrin expression.

PURPOSE: In vivo imaging of α(v)ß(3) has important diagnostic and therapeutic applications. (18)F-Galacto-arginine-glycine-aspartic acid (RGD) has been developed for positron emission tomography (PET) imaging of integrin α(v)ß(3) expression and is now being tested on humans. Dimerization and multimerization of cyclic RGD peptides have been reported to improve the integrin α(v)ß(3)-binding affinity due to the polyvalency effect. Here, we compared a number of new dimeric RGD peptide tracers with the clinically used (18)F-galacto-RGD. PROCEDURES: RGD monomers and dimers were coupled with galacto or PEG(3) linkers, and labeled with (18)F using 4-nitrophenyl 2-(18)F-fluoropropionate ((18)F-NFP) or N-succinimidyl 4-(18)F-fluorobenzoate as a prosthetic group. The newly developed tracers were evaluated by cell-based receptor-binding assay, biodistribution, and small-animal PET studies in a subcutaneous U87MG glioblastoma xenograft model. RESULTS: Starting with (18)F-F(-), the total reaction time for (18)F-FP-SRGD2 and (18)F-FP-PRGD2 is about 120 min. The decay-corrected radiochemical yields for (18)F-FP-SRGD2 and (18)F-FP-PRGD2 are 52 ± 9% and 80 ± 7% calculated from (18)F-NFP. Noninvasive small-animal PET and direct tissue sampling experiments demonstrated that the dimeric RGD peptides had significantly higher tumor uptake as compared to (18)F-galacto-RGD. CONCLUSION: Dimeric RGD peptide tracers with relatively high tumor integrin-specific accumulation and favorable in vivo kinetics may have the potential to be translated into clinic for integrin α(v)ß(3) imaging.

PET imaging with [11C]methyl- L-methionine for therapy monitoring in patients with rectal cancer.

In this study we evaluated whether positron emission tomography (PET) using the amino acid [11C]methyl- L-methionine (MET) may be used for therapy monitoring in patients with rectal cancer who are undergoing preoperative chemoradiotherapy. A total of 41 MET-PET scans were performed in 26 patients with locally advanced rectal cancers. All patients were examined prior to chemoradiotherapy. In 15 patients, MET-PET was repeated after preoperative chemoradiotherapy (45 Gy radiation dose, 250 mg 5-fluorouracil as continuous infusion). MET uptake prior to and after the completion of chemoradiotherapy was correlated with changes in T stage and histopathological regression. All tumours were visualised with high contrast and had a significantly higher SUV (5.7+/-2.2) than normal rectum (2.7+/-0.9) and all other organs in the field of view except the small intestine (3.9+/-1.7). In all tumours studied prior to and after chemoradiotherapy, MET uptake decreased during therapy (SUV before therapy, 6.2+/-2.3; SUV after therapy, 2.6+/-1.2; P=0.0007). However, the degree of change in MET uptake was not correlated with histopathological tumour response. In conclusion, primary rectal cancer can be imaged with MET-PET. However, for the studied chemoradiotherapy regimen, MET-PET did not allow an assessment of the response to therapy.