Tracing proliferating potential of lung tumours by [11C]Nicotinamide

Abstract

Many tumours rely on aerobic glycolysis, known as the Warburg effect, to satisfy energy needs and sustain rapid proliferation [1]. High demands of glucose in tumours can be measured by [¹⁸F[fluorodeoxyglucose, [¹⁸F]FDG, positron emission tomography (PET). Nicotinamide adenine dinucleotide (NAD) is a coenzyme involved in redox reactions in many metabolic pathways, including glycolysis. To maintain the high rates of glycolysis and proliferation, tumours need increased NAD⁺ levels and use nicotinamide for the upregulated NAD⁺ salvage pathway that is the main source of NAD⁺ in proliferative cancer cells [2].  Herein, we show an improved synthesis method of [¹¹C]Nicotinamide, [¹¹C]NAM, and studied the uptake of [¹¹C]NAM and [¹⁸F]FDG to measure proliferating capacity in a lung cancer model.

[Carboxyl-¹¹C]nicotinamide was synthesized by a one-pot radiolabeling method [3] on the SYNTHRA synthesizer (Synthra GmbH, Germany) (see Figure 1A). We used a Kras^G12D/+ genetically engineered mouse model of lung cancer and evaluated the uptake of [¹¹C]nicotinamide and [¹⁸F]FDG with dual-tracer sequential imaging protocol (see Figure 1B) using a NanoScan PET/MRI scanner (Mediso Medical Imaging Systems, Hungary).

We obtained [carboxyl-¹¹C]nicotinamide in a radiochemical yield of 15 ± 5 %, volumic activity of 50 ± 10 MBq/ml, and radiochemical purity was > 99 %.  We optimized the imaging protocol and found the uptake of [¹¹C]nicotinamide co-localized with the uptake of [¹⁸F]FDG in the Kras^G12D/+ model of lung cancer as shown in Figure 1C suggesting the higher NAM uptake was associated with high NAD⁺ production in highly proliferating tumours.

We demonstrated that metabolic PET/MRI imaging with [¹¹C]NAM can complement [¹⁸F]FDG PET and be useful for probing proliferative potential in lung cancer. This method could be translated and applied in clinical practice to enable visualization of NAD⁺ metabolism in lung tumours and targeted therapeutically.

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