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Mapping Extracellular pH in Rat Brain Gliomas in Vivo by ¹ H Magnetic Resonance Spectroscopic Imaging: Comparison with Maps of Metabolites^,1

Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Cientificas, 28029 Madrid, Spain [M-L. G-M., S.C.]; Unité mixte Institut National de la Santé et de la Recherche Médicale/Université Joseph Fourier: U438 "RMN Bioclinique," Laboratoire de Recherche Correspondant du Commissariat à l’Energie Atomique, Centre Hospitalier Universitaire BP 217, 38043 Grenoble, France [G. H., C. R., R. F., J. A. C., A. Z.]; and Departemento de Química Orgánica y Biología, Facultad de Ciencias, Universidad Nacional de Educación a Distancìa, 28040 Madrid, Spain [P. B.]

The value of extracellular pH (pH_e) in tumors is an important factor in prognosisand choice of therapy. We demonstrate here that pH_e can be mappedin vivo in a rat brain glioma by ¹H magnetic resonance spectroscopic imaging (SI) of the pH buffer (±)2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA). ¹H SI also allowed us to map metabolites, and, to better understand the determinants of pH_e, we compared maps of pH_e, metabolites, and the distribution of the contrast agent gadolinium1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraaceticacid (Gd-DOTA). C6 cells injected in caudate nuclei of four Wistar rats gave rise to gliomas of 10 mm in diameter. Three mmols of IEPA were injected in the right jugular vein from t = 0 to t = 60 min. From t = 50 min to t = 90 min, spin-echo ¹H SI was performed with an echo time of 40 ms in a 2.5-mm slice including the glioma (nominal voxel size, 2.2 µl). IEPA resonances were detected only within the glioma and were intense enough for pH_e to be calculated from the chemical shift of the H2 resonance in almost all voxels of the glioma. ¹H spectroscopic images with an echo time of 136 ms were then acquired to map metabolites: lactate, choline-containing compounds (tCho), phosphocreatine/creatine, and N-acetylaspartate. Finally, T₁-weighted imaging after injection of a bolus of Gd-DOTA gave a map indicative of extravasation. On average, the gradient of pH_e (measured where sufficient IEPA was present) from the center to the periphery was not statistically significant. Mean pH_e was calculated for each of the four gliomas, and the average was 7.084 ± 0.017 (± SE; n = 4 rats), which is acid with respect to pH_e of normal tissue. After normalization of spectra to their water peak, voxel-by-voxel comparisons of peak areas showed that N-acetylaspartate, a marker of neurons, correlated negatively with IEPA (P < 0.0001) and lactate (P < 0.05), as expected of a glioma surrounded by normal tissue. tCho (which may indicate proliferation) correlated positively with pH_e (P < 0.0001). Lactate correlated positively with tCho (P < 0.0001), phosphocreatine/creatine (P < 0.001), and Gd-DOTA (P < 0.0001). Although lactate is exported from cells in association with protons, within the gliomas, no evidence was observed that pH_e was significantly lower where lactate concentration was higher. These results suggest that lactate is produced mainly in viable, well-perfused, tumoral tissue from which proton equivalents are rapidly cleared.

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