Reserpine-induced rat model for depression: Behavioral, physiological and PET-based dopamine receptor availability validation.

BACKGROUND: Reserpine (RES), a Vesicular Monoamine Transporter 2 (VMAT2) inhibitor agent, has been used in preclinical research for many years to create animal models for depression and to test experimental antidepressant strategies. Nevertheless, evidence of the potential use and validity of RES as a chronic pharmacological model for depression is lacking, and there are no comprehensive studies of the behavioral effects in conjunction with molecular outcomes. METHODS: Experiment 1. Following baseline behavior testing sensitive to depression-like phenotype and locomotion (Phase 1), 27 Sprague-Dawley (SD) rats received i.p. either vehicle solution (0.0 mg/kg), low (0.2 mg/kg) or high (0.8 mg/kg) RES dose for 20 days using a pre-determined schedule and reassessed for behavioral phenotypes (Phase 2). After 10 days washout period, and a final behavioral assessment (Phase 3), the brains were collected 16 days after the last injection for mRNA-expression assessment. Experiment 2. In a similar timetable as in Experiment 1 but without the behavioral testing, 12 SD rats underwent repetitive dopamine D2/3 receptor PET scanning with [18F]DMFP following each Phase. The binding potential (BPND) of [18F]DMFP was quantified by kinetic analysis as a marker of striatal D2/3R availability. Weight and welfare were monitored throughout the study. RESULTS: Significant, dose-dependent weight loss and behavioral deficits including both motor (hypo-locomotion) and non-motor behavior (anhedonia, mild anxiety and reduced exploration) were found for both the low and high dose groups with significant decrease in D2R mRNA expression in the accumbal region for the low RES group after Phase 3. Both RES treated groups showed substantial increase in [18F]DMFP BPND (in line with dopamine depletion) during Phase 2 and 3 compared to baseline and Controls. CONCLUSIONS: The longitudinal design of the study demonstrated that chronic RES administration induced striatal dopamine depletion that persisted even after the wash-out period. However, the behavior phenotype observed were transient. The data suggest that RES administration can induce a rodent model for depression with mild face validity.

Convenient Preparation of 18F-Labeled Peptide Probes for Potential Claudin-4 PET Imaging.

Since pancreatic cancer is often diagnosed in a late state of cancer development, diagnostic opportunities allowing early disease detection are highly sought after. As such, cancer expression of claudin proteins is markedly dysregulated, making it an attractive target for molecular imaging like positron emission tomography (PET). Claudins are a family of transmembrane proteins that have a pivotal role as members of the tight junctions. In particular, claudin-3 and claudin-4 are frequently overexpressed in pancreatic cancer. 18F-Labeled claudin selective peptides would provide access to a novel kind of imaging tools for pancreatic cancer. In this work we describe the synthesis of the first 18F-labeled probes potentially suitable for PET imaging of claudin-4 expression. These probes were prepared using oxime ligation of 5-[18F]fluoro-5-deoxyribose (5-[18F]FDR) to claudin selective peptides. As a proof-of-principle, one of them, 5-[18F]FDR-Clone 27, was isolated in >98% radiochemical purity and in 15% radiochemical yield (EOB) within 98 min, and with a molar activity of 4.0 GBq/µmol (for 30 MBq of tracer). Moreover, we present first biological data for the prepared 5-FDR-conjugates. These tracers could pave the way for an early diagnosis of pancreatic tumor, and thus improve the outcome of anticancer therapy.