Imaging Experimental Brain Tumors with 1-Aminocyclopentane Carboxylic Acid and Alpha-Aminoisobutyric Acid: Comparison to Fluorodeoxyglucose and Diethylenetriaminepentaacetic Acid in Morphologically Defined Tumor Regions

The goal of this study was to evaluate the differences and define the advantages of imaging experimental brain tumors in rats with two nonmetabolized amino acids, 1-aminocyclopentane carboxylic (ACPC) acid and α-aminoisobutyric (AIB) acid compared with imaging with fluorodeoxyglucose (FDG) or the gallium-diethylenetriaminepentaacetic acid chelate (Ga-DTPA). 1-aminocyclopentane carboxylic acid, AIB, and FDG autoradiograms were obtained 60 minutes after intravenous injection to simulate positron emission tomography (PET) imaging, whereas the Ga-DTPA autoradiograms were obtained 5 or 10 minutes after injection to simulate gadolinium (Gd)-DTPA–enhanced magnetic resonance (MR) images. Three experimental tumors were studied (C6, RG2, and Walker 256) to provide a range of tumor types. Triple-label quantitative autoradiography was performed, and parametric images of the apparent distribution volume (Va, mL/g) for ACPC or AIB, relative glucose metabolism (R, μmol/100 g/min), vascular permeability to Ga-DTPA (K1, μL/min/g), and histology were obtained from the same tissue section. The four images were registered in an image array processor, and regions of interest in tumor and contralateral brain were defined on morphologic criteria (histology) and were transferred to the autoradiographic images. A comparative analysis of all measured values was performed. The location and morphologic characteristics of the tumor had an effect on the images and measurements of Va, R, and K1. Meningeal extensions of all three tumors consistently had the highest amino acid uptake (Va) and vascular permeability (K1) values, and subcortical portions of the tumors usually had the lowest values. Va and R (FDG) values generally were higher in tumor regions with high-cell density and lower in regions with low-cell density. Tumor areas identified as “impending” necrosis on morphologic criteria consistently had high R values, but little or no change in Va or K1. Tumor necrosis was seen consistently only in the larger Walker 256 tumors; low values of R and Va for AIB (less for ACPC) were measured in the necrotic-appearing regions, whereas K1 was not different from the mean tumor value. The highest correlations were observed between vascular permeability (K1 for Ga-DTPA) and Va for AIB in all three tumors; little or no correlation between vascular permeability and R was observed. The advantages of ACPC and AIB imaging were most convincingly demonstrated in C6 gliomas and in Walker 256 tumors. 1-aminocyclopentane was substantially better than FDG or Ga-DTPA for identifying tumor infiltration of adjacent brain tissue beyond the macroscopic border of the tumor; ACPC also may be useful for identifying low-grade tumors with an intact blood–brain barrier. Contrast-enhancing regions of the tumors were visualized more clearly with AIB than with FDG or Ga-DTPA; viable and necrotic-appearing tumor regions could be distinguished more readily with AIB than with FDG. [11C]-labeled ACPC and AIB are likely to have similar advantages for imaging human brain tumors with PET.

Tumor-associated neurological dysfunction prevented by lazaroids in rats

✓ The efficacy of U-74006F and U-78517F in the treatment of blood-tumor barrier permeability and tumor-associated neurological dysfunction was evaluated in a brain-tumor model in rats. U-74006F is a 21-aminosteroid and U-78517F is a 2-methylamino chroman. Rats with stereotactically implanted Walker 256 tumors were treated with methylprednisolone, U-74006F, U-78517F, or vehicle (0.05 N HCl) on Days 6 through 10 following implantation. Neurological function and vascular permeability were assessed on Day 10. Methylprednisolone and U-74006F were equally effective at preventing neurological dysfunction compared to the control group (p < 0.01); U-78517F was slightly less effective than U-74006F and methylprednisolone but was significantly better than vehicle in preventing neurological dysfunction. Delivery of methylprednisolone resulted in a significant decrease in tumor vascular permeability (p < 0.006) while U-74006F and U-78517F had no effect on permeability. This suggests that U-74006F and U-78517F prevented tumor-associated neurological dysfunction by a mechanism other than decreasing permeability in tumor capillaries, and that U-74006F or U-78517F could prove useful in the treatment of brain tumors.

Imaging Peripheral Benzodiazepine Receptors in Brain Tumors in Rats: In vitro Binding Characteristics

Peripheral benzodiazepine binding constants for transplanted RG-2 gliomas and HK and LK Walker 256 tumors (metastatic breast carcinoma) were determined in Wistar rats using autoradiography. In addition, Kd and Bmax parameters for peripheral benzodiazepine receptors on RG-2 tumors were directly visualized using digital image analysis of autoradiograms. High specific binding of [3H]PK11195, a selective peripheral benzodiazepine ligand, had excellent topographical correlation to areas of histologically verified tumor. Scatchard analysis suggested a single class of peripheral binding sites with similar binding affinities in RG-2 and LK Walker 256 tumors and normal cortex. Bmax was 20-fold greater in glial tumors and 11.6- and 10.6-fold greater in LK and HK Walker 256 tumors, respectively, compared to normal cortex. The location of metastatic tumors, either intracerebrally or subcutaneously, did not effect their Kd or Bmax values. Kd and Bmax values for RG-2 tumors were similar whether determined densitometrically or by direct visualization with image analysis. Binding parameters within normal brain were difficult to visualize by image analysis due to the low level of specific binding. The ability to label specifically intracerebral tumor cells and to characterize the binding parameters shown in this study suggest that peripheral benzodiazepine receptor ligands could be utilized by PET to analyze directly a variety of tumors in humans.