Siponimod (BAF312) penetrates, distributes, and acts in the central nervous system: Preclinical insights.

BACKGROUND: Siponimod (BAF312), a selective S1P1/S1P5 agonist, reduces disability progression in secondary progressive MS. Recent observations suggest it could act via S1P1/S1P5-dependent anti-inflammatory and pro-myelination effects on CNS-resident cells. OBJECTIVE: Generate preclinical evidence confirming siponimod's CNS penetration and activity. METHODS: Siponimod's CNS penetration and distribution was explored in rodents and non-human primates (NHPs) using: Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS), quantitative whole-body autoradiography (QWBA) using 14C-radiolabeled siponimod or non-invasive single-photon emission CT (SPECT) with a validated 123I-radiolabeled siponimod analog. Functional CNS activity was investigated by S1P1 receptor quantification in brain homogenates. RESULTS: In mice/rats, siponimod treatments achieved dose-dependent efficacy and dose-proportional increase in drug blood levels, with mean brain/blood drug-exposure ratio (Brain/BloodDER) of 6-7. Efficacy in rat brain tissues was revealed by a dose-dependent reduction in brain S1P1 levels. QWBA distribution analysis in rats indicated that [14C]siponimod related radioactivity could readily penetrate CNS, with particularly high uptakes in white matter of cerebellum, corpus callosum, and medulla oblongata versus lower exposures in other areas such as olfactory bulb. SPECT monitoring in NHPs revealed CNS distribution with a brain/bloodDER of ∼6, as in rodents. CONCLUSION: Findings demonstrate siponimod's CNS penetration and distribution across species, with high translational potential to human.

A case report of an uncommon presentation of 99mtechnetium pyrophosphate scintigraphy in transthyretin cardiac amyloidosis: A potential diagnostic pitfall, pseudo-positive or pseudo-negative?

99mTechnetium pyrophosphate (99mTc-PYP) scintigraphy has shown utility for diagnosis of transthyretin (ATTR) cardiac amyloidosis with a high sensitivity and specificity. However, in clinical practice, a protocol and a method of analysis of this modality are not yet unified. We present a case of ATTR cardiac amyloidosis showing a positive cardiac uptake in planar imaging but no myocardial uptake in single-photon emission computed tomography/computed tomography (SPECT/CT) fusion imaging on 99mTc-PYP scintigraphy. We considered this tracer accumulation in the cardiac blood pool to be an inconclusive study. In this report, we focus on an inconclusive study case as a potential pitfall of 99mTc-PYP scintigraphy and discuss the interpretation of 99mTc-PYP scintigraphy findings with using both planar and SPECT/CT imaging for improvement of diagnostic accuracy for ATTR cardiac amyloidosis. .