Indication for different mechanisms of kidney uptake of radiolabeled peptides.

UNLABELLED: Nephrotoxicity due to renal reabsorption of radiolabeled peptides limits the tumor dose in peptide receptor radiotherapy (PRRT). Therefore, we evaluated the ability of several agents to inhibit the renal accumulation of different radiopeptides. METHODS: Male Wistar rats (4 per group) were injected intravenously with 1 MBq of (111)In-labeled octreotide (OCT), minigastrin (MG), bombesin (BOM), or exendin (EX), together with a potential inhibitor of renal uptake (lysine [Lys], poly-glutamic acid [PGA], and Gelofusine [GF], a gelatin-based plasma expander) or phosphate-buffered saline as a control. Organ uptake at 20 h after injection was determined as the percentage of injected activity per gram (%IA/g). Lys, PGA, and GF were also combined to determine whether an additive effect could be obtained. The localization of the peptides in the kidneys was investigated by autoradiography using a phosphor imager. RESULTS: OCT accumulation in the kidney was inhibited by Lys and GF (40.7%-45.1%), whereas PGA was ineffective. On the other hand, renal uptake of BOM, MG, and EX was inhibited by PGA and GF (15.4%-85.4%), whereas Lys was ineffective. The combination of GF and Lys showed additive effects in inhibiting OCT uptake, whereas PGA and GF had additive effects for the inhibition of EX uptake. The amount of kidney uptake correlated with the number of charged amino acids. All radiopeptides were localized in the renal cortex, as indicated by autoradiography. CONCLUSION: Inhibition of renal accumulation of the radiopeptides tested could be achieved by either Lys or PGA but not by both at the same time, suggesting 2 different uptake mechanisms. The differences in renal accumulation of radiopeptides may be related to the number of charges of a molecule. GF is the only compound that inhibited renal accumulation of all radiopeptides tested. Additional experiments are needed to further elucidate these findings and to optimize inhibition of renal accumulation of radiopeptides to reduce the kidney dose in PRRT.

A new technique for in vivo imaging of specific GLP-1 binding sites: first results in small rodents.

EXPERIMENTAL OBJECTIVES: In vivo imaging of GLP-1 receptor-positive tissues may allow examination of physiologic and pathophysiologic processes. Based on the GLP-1 analog Exendin 4, we have developed a radiolabeled compound specifically targeting the GLP-1 receptor (DTPA-Lys40-Exendin 4). This work aims to detect GLP-1 receptor-positive tissues by biodistribution studies and in vivo small animal imaging studies. For in vivo imaging, a high-resolution multi-pinhole SPECT (single photon emission computed tomography) system was used in conjunction with an MRI (magnetic resonance imaging) system for image fusion. RESULTS: DTPA-Lys40-Exendin 4 can be labeled with 111In to high specific activity (40 GBq/micromol). The radiochemical purity reliably exceeded 95%. Using this compound for in vivo small animal imaging of rats and mice as well as for biodistribution studies, specific GLP-1 binding sites could be detected in stomach, pancreas, lung, adrenals, and pituitary. Receptor-positive tissues were visualized with a high-resolution SPECT system with a resolution of less than 1 mm. CONCLUSIONS: The new technique using DTPA-Lys40-Exendin 4 allows highly sensitive imaging of GLP-1 receptor-positive tissues in vivo. Therefore, intra-individual follow-up studies of GLP-1 receptor-positive tissue could be conducted in vivo.

Tracers to monitor the response to chemotherapy: in vitro screening of four radiopharmaceuticals.

OBJECTIVES: It has been postulated that radiopharmaceuticals can be used to predict the therapeutic response to (chemo)therapy, which could lead to individualized treatment regimens. In this study, 18F-deoxyglucose, 99mTc-tetrofosmin, 125I-deoxyuridineribose, and 125I-methyltyrosine were tested for this purpose. METHODS: The uterine sarcoma cell line MES-SA (MDR-) and its multidrug resistant variant, MES-SA/Dx5 (MDR+), were used. The MDR+ cells express high levels of P-glycoprotein, which makes them relatively resistant to various chemotherapeutic agents. Cells were cultured in the presence of escalating concentrations of doxorubicin, and the cellular uptake of the radiopharmaceuticals was determined. RESULTS: Decreasing 18F-deoxyglucose uptake at escalating doxorubicin concentrations reflected the chemosensitivity of the cells: 18F-deoxyglucose uptake in the MDR- cells was reduced to 40% of the baseline level in the presence of 1 microM of doxorubicin, compared to 74% in the MDR+ cells. The 125I-deoxyuridineribose uptake in MDR- cells was reduced to 2% of the baseline level when cultured at a concentration of 1 microM of doxorubicin, while this was 79% in the MDR+ cells. The same trend was observed with 125I-methyltyrosine. The enhanced doxorubicin chemosensitivity of MDR+ cells in the presence of verapamil, a modulator of P-glycoprotein, was reflected by the reduced uptake of 18F-deoxyglucose, 125I-deoxyuridineribose, and 125I-methyltyrosine. Furthermore, baseline 99mTc-tetrofosmin uptake in MDR+ cells was more than six-fold lower than in MDR- cells. CONCLUSION: In the presence of doxorubicin, the uptake of 18F-deoxyglucose, 125I-deoxyuridineribose and, to a lesser extent, 125I-methyltyrosine is more pronouncedly reduced in MDR- cells than in MDR+ cells. The reversal of doxorubicin-resistance of MDR+ cells by verapamil was also reflected by the uptake of 18F-deoxyglucose, 125I-deoxyuridineribose, and 125I-methyltyrosine. 99mTc-tetrofosmin uptake reflected P-glycoprotein expression without exposure to doxorubicin.