Radiosynthesis and Preclinical Investigation of ¹¹C‐Labelled 3‐(4,5‐Diphenyl‐1,3‐oxazol‐2‐yl)propanal Oxime ([¹¹C]SZV 1287)

Abstract

The radiosynthesis, as well as the in vivo and ex vivo biodistribution of the 11C radiolabelled 3‐(4,5‐diphenyl‐1,3‐oxazol‐2‐yl)propanal oxime (6, [11C]SZV 1287) are reported. SZV 1287 is a novel semicarbazide‐sensitive amine oxidase (SSAO) inhibitor and a promising candidate to be a novel analgesic for the treatment of neuropathic pain. Its radiolabelling was developed via a four‐step radiosynthesis which started from the reaction of a Grignard reagent with [11C]CO2 to produce [11C]oxaprozin (3). In the next step this carboxylic acid 3 was directly reduced to yield the corresponding aldehyde, which was then converted into the oxime. [11C]SZV 1287 was administered to male NMRI mice. The animals were examined with dynamic PET/MR imaging for 90 minutes. Biodistribution studies were performed at 10, 30, 60 and 120 minutes post injection. The accumulation of the labelled compound was observed in the brain of the animals. The main excretion pathway was found to be through the liver and intestines. These studies provide preliminary information for pharmacokinetic characterization of the SZV 1287.

Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain

“…However, the observed inhibitory effect is unlikely to result from oxaprozin, but SZV 1287 itself, because oxaprozin was previously ineffective in the same model [20]. We also showed the brain penetration of SZV 1287 with HPLC analysis supporting our previous PET/MR imaging data [22]. Although brain concentrations were relatively low in all effective SZV 1287 doses, these were sufficient to produce an analgesic effect, which could be explained by the irreversible mode of action of SZV 1287 resulting in complete AOC3 inhibition already in the detected low concentrations.…”

“…We provide here the proof-of-concept that our novel multi-target drug candidate SZV 1287 administered in an enterosolvent preparation planned for the phase I clinical trial inhibits neuropathic mechanical hyperalgesia in mice. It rapidly penetrates the brain as shown by HPLC analysis supporting our previous PET/MR imaging data [22], which suggests at least partially a central mechanism of action involved in its analgesic effect. We demonstrated its thermoregulatory safety despite its ability to antagonize the TRPV1 receptor [10].…”

“…administration in two different arthritis models and in an inflammation-independent traumatic neuropathy model [19,20], in which its main metabolite, oxaprozin, was ineffective [20]. The ability of SZV 1287 to inhibit neuropathic mechanical hyperalgesia suggests that it exerts a central mechanism of action, which was recently supported by in vivo dynamic positron emission tomography/magnetic resonance (PET/MR) imaging results demonstrating rapid blood-brain barrier penetration [22].…”

Carbon Dioxide Radical Anion by Photoinduced Equilibration between Formate Salts and [11C, 13C, 14C]CO2: Application to Carbon Isotope Radiolabeling

“…When the standard reaction conditions were applied with [ 11 C]CO 2 , a 8% radiochemical conversion (RCC) was observed. After optimization, an excess of formate (5.5 equiv in respect to styrene) under 41 To show concrete evidence of the utility of the approach for in vivo imaging, the whole-body PET biodistribution profile of [ 11 C]oxaprozin was investigated in mice (Scheme 7A). The time−activity curves (TACs) depict a rapid uptake of [ 11 C]10d in the heart, liver, and kidney followed by a slow distribution phase (Scheme 7B).…”

“…It is important to highlight that [ 11 C]­10d has previously been labeled by Szikra et al. in a two-step sequence from a Grignard precursor …”