Feasibility of imaging pentose cycle glucose metabolism in gliomas with PET: Studies in rat brain tumor models

The feasibility of imaging pentose cycle (PC) glucose utilization in human gliomas with PET was explored in two rat glioma models by means of glucose radiolabeled in either the carbon-1 (C-1) or carbon-6 (C-6) position. Methods: In vitro, monolayers of T-36B-10 glioma, tissue slices of intracerebral glioma grafts or slices of normal brain were fed [1- ¹⁴C]glucose or [6-¹⁴C]glucose, and the generated [¹⁴C]CO₂ was trapped to quantitate the ratio of [¹⁴C]CO₂ from ¹⁴C-1 versus ¹⁴C-6. In vivo, rats bearing grafts of either T-36B-10 or T-C6 rat gliomas at six subcutaneous sites received simultaneous intravenous injections of either [1- ¹¹C]glucose and [6-¹⁴C]glucose, or [1-¹⁴C]glucose and [6-¹¹C]glucose. Tumors were excised between 5 and 55 min postinjection to quantify tracer uptake while arterial plasma was collected to derive time-activity input curves. Results: In vitro, the C-1/C-6 ratio for CO₂ production from T-36B- 10 monolayers was 8.8 ± 0.4 (s.d.), in glioma slices it was 6.1 ± 2.1 and in normal brain slices it was 1.1 ± 0.7. PC metabolism in T-36B-10 was 1.8% ± 0.5 of total glucose utilization. In vivo, tumor radioactivity levels normalized by plasma isotopic glucose levels showed that retained C-1 relative to C-6 radiolabeled glucose was significantly lower in both gliomas, 4.9% lower in T-36B-10 (p < 0.01) and 4.7% lower in T-C6 (p < 0.01). In an additional group of rats bearing T-36B-10 gliomas and exposed to 10 Gy of ¹³⁷Cs irradiation 4 hr before isotope injection, the C-1 level was 5.6% lower than that for C-6 (p < 0.05). These results were analyzed with a model of glucose metabolism that simultaneously optimized parameters for C-1 and C- 6 glucose kinetics by simulating the C-1 and C-6 tumor time-activity curves. The rate constant for loss of radiolabeled carbon from the tumors, κ4, was higher for C-1 than for C-6 in all groups of rats (19% higher for T-36B-10 unirradiated, 32% for T-36B-10 irradiated and 32% for T-C6 unirradiated). Conclusion: Mathematical modeling, Monte Carlo simulations and construction of receiver-operator-characteristic curves show that if human gliomas have a similar fractional use of the PC, it should be measurable with PET using sequential studies with [1-¹¹C]glucose and [6-¹¹C]glucose.