Radiosynthesis and Preliminary Evaluation of [11C]SSI-4 for the Positron Emission Tomography Imaging of Stearoyl CoA Desaturase 1

Stearoyl CoA desaturase 1 (SCD1) is the rate-limitingenzyme forconverting saturated fatty acids (SFAs) into monounsaturated fattyacids (MUFAs) and plays a key role in endogenous (de novo) fatty acidmetabolism. Given that this pathway is broadly upregulated acrossmany tumor types with an aggressive phenotype, SCD1 has emerged asa compelling target for cancer imaging and therapy. The ligand 2-(4-(2-chlorophenoxy)piperidine-1-carboxamido)-N-methylisonicotinamide (SSI-4) was identified as a potentand highly specific SCD1 inhibitor with a strong binding affinityfor SCD1 at our laboratory. We herein report the radiosynthesis of[C-11]SSI-4 and the preliminary biological evaluation including in vivo PET imaging of SCD1 in a human tumor xenograft model.Radiotracer [C-11]SSI-4 was labeled at the carbamide positionvia the direct [C-11]CO2 fixation on the SynthraMeIplus module in high molar activity and good radiochemical yield. In vitro cell uptake assays were performed with three hepatocellularcarcinoma (HCC) cell lines and three renal cell carcinoma (RCC) celllines. Additionally, in vivo small animal PET/CTimaging with [C-11]SSI-4 and the biodistribution were carriedout in a mouse model bearing HCC xenografts. Radiotracer [C-11]SSI-4 afforded a 4.14 & PLUSMN; 0.44% (decay uncorrected, n = 10) radiochemical yield based on starting [(11)]CO2 radioactivity. The [C-11]SSI-4 radiosynthesistime including HPLC purification and SPE formulation was 25 min fromthe end of bombardment to the end of synthesis (EOS). The radiochemicalpurity of [C-11]SSI-4 was 98.45 & PLUSMN; 1.43% (n = 10) with a molar activity of 225.82 & PLUSMN; 33.54 GBq/& mu;mol(6.10 & PLUSMN; 0.91 Ci/& mu;mol) at the EOS. In vitro cell uptake study indicated all SSI-4 responsive HCC and RCC cellline uptakes demonstrate specific uptake and are blocked by standardcompound SSI-4. Preliminary small animal PET/CT imaging study showedhigh specific uptake and block of [C-11]SSI-4 uptake withco-injection of cold SSI-4 in high SCD1-expressing organs includinglacrimal gland, brown fat, liver, and tumor. In summary, novel radiotracer[C-11]SSI-4 was rapidly and automatedly radiosynthesizedby direct [C-11]CO2 fixation. Our preliminarybiological evaluation results suggest [C-11]SSI-4 couldbe a promising radiotracer for PET imaging of SCD1 overexpressingtumor tissues.