[en] Aim: Sigma receptors which are expressed in the brain as well as in endocrine and immune systems have been the focus of research in the past few years due to their implicated role in psychosis. Many widely used antipsychotics interact with sigma receptors, some exhibit sigma receptor antagonism as their predominant mode of action. There is evidence that sigma receptors modulate several neuroreceptors, including dopaminergic and other catecholaminergic systems. Furthermore there are indications that a decrease of cortical sigma receptors occurs in schizophrenia. They are also present in high densities in various human and rodent cancer cell lines. In light of these findings we report the synthesis and in vivo evaluation of a ¹²³I-labelled selective sigma ligand. Materials and Methods: The ¹²³I-labelled compound was synthesized by electrophilic iododestannylation of the tributyltin derivative. For biodistribution studies 37 kBq of the ¹²³I-labelled compound dissolved in a mixture water/ethanol (99/1) was injected i.v. into the tail vein of NMRI mice. At various time points p.i. the mice were sacrificed and dissected. Biodistribution studies were performed until 48 hours p.i.. For blocking studies the mice were injected with cold product (1mg/kg) 10 minutes before tracer injection. Regional brain distributions were carried out in New Zealand rabbits, for this study 9,25 MBq of the ¹²³I-labelled compound dissolved in a mixture water/ethanol (90/10) was injected i.v. into the ear vein. At various time points up to 1 hour post injection the rabbits were sacrificed and their brain was dissected. Subsequently a regional blocking study was preformed in rabbits using the sigma ligand 1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)-piperidine (FPS)(0,5 mg/kg) which was injected 5 minutes before tracer injection. Results: Radiochemical yield was 70% ± 5%. Radiochemical purity was >95%. Biodistribution studies showed penetration through the blood brain barrier and accumulation in the brain (ratio brain to blood after 10 min: 10). Pretreatment with cold product resulted in a decrease of accumulation of the tracer in the brain (ratio brain to blood after 10 min: 1.6). As expected the regional brain distribution showed a homogeneous distribution throughout the brain, pretreatment with FPS resulted in a decrease of the uptake in different brain regions (cortex: 91%, striatum: 88% and hypothalamus: 89% decrease). Conclusion: Both biodistribution and blocking studies in mice and rabbits show that ¹²³I-4-iodo-N-(4-(4-(2-methoxyphenyl)-1-piperazinyl)butyl)-benzamide is a potential tracer for in vivo visualization of the sigma receptor

[en] Aim: Matrix metalloproteinases (MMPs) are a family of at least 18 secreted and membrane-bound zinc endopeptidases. Collectively they function in the degradation of extracellular matrix proteins and play an important role in both normal and pathological tissue remodelling. Increased MMP activity is detected in a wide range of cancers and seems to be correlated to their invasive and metastatic potential. MMPs thus seem an attractive target for both diagnostic (SPECT tracer) and therapeutic purposes. Therefore, we synthesised a ¹²³I-labelled MMP 2 inhibitor and evaluated it in vitro. Materials and methods: The ¹²³I-labelled compound was synthesised by a Cu-assisted nucleophilic non-isotopic exchange starting from Br-BSP. After reaction, the mixture was purified by HPLC. IC₅₀ values were obtained by in vitro enzyme assays. A 1:1 mix between non-radiolabelled inhibitor (concentration range: 300 nM - 0.05 nM) and enzymes (MMP2, cMT1-MMP, cMT3-MMP) was incubated for 15 minutes at 37⁰C. The fluorescent substrate (Mca-Pro-Leu-Gly-Leu-Dap(Dnp)-Ala-Arg-NH2) was added and the increase of fluorescence versus time, due to the hydrolysis of substrate, was measured (GEMINI-XS, λ_exc = 328 nm and λ_em = 393nm). Initial velocities were calculated for different concentrations of inhibitor and the IC₅₀ values were then determined. Results: Radiochemical yield was 30% ±3%. Radiochemical purity was >95%. IC₅₀ values for inhibition of MMP2, cMT3-MMP and cMT1-MMP were 0.5 nM, 7.1 nM and 16.9 nM respectively. Conclusion: ¹²³I-BSP was synthesised with 30% ±3% yield. After HPLC the radiochemical purity was >95%. In vitro enzyme assays of I-BSP showed an inhibition of MMP2, cMT3-MMP and cMT1-MMP in the low nM range (0.5 nM, 7.1 nM and 16.9 nM respectively). In vivo studies (biodistribution, metabolizing) in mice will be performed in the near future