SSI-4

Stearoyl CoA desaturase 1 (SCD1) is the rate-limiting enzyme for converting saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs) and plays a key role in endogenous (de novo) fatty acid metabolism. Given that this pathway is broadly upregulated across many tumor types with an aggressive phenotype, SCD1 has emerged as a compelling target for cancer imaging and therapy. The ligand 2-(4-(2-chlorophenoxy)piperidine-1-carboxamido)-N-methylisonicotinamide (SSI-4) was identified as a potent and highly specific SCD1 inhibitor with a strong binding affinity for SCD1 at our laboratory. We herein report the radiosynthesis of [¹¹C]SSI-4 and the preliminary biological evaluation including in vivo PET imaging of SCD1 in a human tumor xenograft model. Radiotracer [¹¹C]SSI-4 was labeled at the carbamide position via the direct [¹¹C]CO₂ fixation on the Synthra MeIplus module in high molar activity and good radiochemical yield. In vitro cell uptake assays were performed with three hepatocellular carcinoma (HCC) cell lines and three renal cell carcinoma (RCC) cell lines. Additionally, in vivo small animal PET/CT imaging with [¹¹C]SSI-4 and the biodistribution were carried out in a mouse model bearing HCC xenografts. Radiotracer [¹¹C]SSI-4 afforded a 4.14 ± 0.44% (decay uncorrected, n = 10) radiochemical yield based on starting [¹¹]CO₂ radioactivity. The [¹¹C]SSI-4 radiosynthesis time including HPLC purification and SPE formulation was 25 min from the end of bombardment to the end of synthesis (EOS). The radiochemical purity of [¹¹C]SSI-4 was 98.45 ± 1.43% (n = 10) with a molar activity of 225.82 ± 33.54 GBq/μmol (6.10 ± 0.91 Ci/μmol) at the EOS. In vitro cell uptake study indicated all SSI-4 responsive HCC and RCC cell line uptakes demonstrate specific uptake and are blocked by standard compound SSI-4. Preliminary small animal PET/CT imaging study showed high specific uptake and block of [¹¹C]SSI-4 uptake with co-injection of cold SSI-4 in high SCD1-expressing organs including lacrimal gland, brown fat, liver, and tumor. In summary, novel radiotracer [¹¹C]SSI-4 was rapidly and automatedly radiosynthesized by direct [¹¹C]CO₂ fixation. Our preliminary biological evaluation results suggest [¹¹C]SSI-4 could be a promising radiotracer for PET imaging of SCD1 overexpressing tumor tissues.

The adaptation effect refers to the gradual reduction of dysfluencies with repeated exposure to a substance. The concept of adaptation was originally defined in light of the reading task. Yet, limited studies have also confirmed the adaptation effect in spontaneous-speech. The reduction in the dysfluencies can be attributed to the reduction in the anxiety, or getting habituated to the content of reading material or due to motor learning.

This research aimed at measuring the adaptation effect in real and virtual reality (VR) environments for spontaneous-speech and reading. The objectives were divided into two categories. The first objective aimed at comparing the adaption effect for the real and VR environments on the reading task, while the second objective addressed the same objective, but for the spontaneous-speech task. The study involved 24 participants in the age range of 19-33 years. SSI-4 was administered on the participants.

The reduction in dysfluencies was seen for both real and VR testing environments. The reduction in the dysfluency was more marked for reading-task compared to spontaneous-speech task. The results shed light on the relationship between adaptation effect and the test environment.