PET Imaging Evaluation of Four σ₁ Radiotracers in Nonhuman Primates

Abstract

The σ receptors (S1Rs) are implicated in a variety of diseases including Alzheimer disease and cancer. Previous PET S1R radiotracers are characterized by slow kinetics or off-target binding that impedes their use in humans. Here, we report the first PET imaging evaluation in rhesus monkeys of 4 F-labeled spirocyclic piperidine-based PET radiotracers (F- to F-). Baseline scans for the 4 radiotracers were obtained on an adult male rhesus monkey. Blocking scans were obtained with the S1R-selective agonist SA4503 to assess binding specificity ofF- and F- Arterial input functions were measured, and binding parameters were determined with kinetic modeling analysis. In the rhesus brain, all 4 radiotracers showed high and fast uptake. Tissue activity washout was rapid forF- and F-, and much slower for F- and F-, in line with their respective in vitro S1R-binding affinities. Both the 1-tissue-compartment and multilinear analysis-1 kinetic models provided good fits of time-activity curves and reliable estimates of distribution volume. Regional distribution volume values were highest in the cingulate cortex and lowest in the thalamus for all radiotracers. F- showed greater differential uptake across brain regions and 3-fold-higher binding potential than F- SA4503 at the dose of 0.5 mg/kg blocked approximately 85% (F-) and 95% (F-) of radiotracer binding. TracersF- and F- displayed high brain uptake and fast tissue kinetics, with F- having higher specific binding signals than F- in the same monkey. Taken together, these data indicate that both F- and F- possess the requisite kinetic and imaging properties as viable PET tracers for imaging S1R in the human brain.

Evaluation of 18F-IAM6067 as a sigma-1 receptor PET tracer for neurodegeneration in vivo in rodents and in human tissue

“…Although affinity and selectivity are essential criterion, in vivo pharmacokinetics is an equally important parameter as recent studies have shown that 18 F-FTC-146 had unfavourably slow pharmacokinetic properties for human use 30 , 31 . Noteworthily, it was shown in non-human primate that despite having lower affinity (S)- 18 F-fluspidine (K i = 2.30 nM) displayed more favourable pharmacokinetics for human use than (R)- 18 F-fluspidine (K i = 0.52 nM) 32 . Hence, taking into account all these considerations, to date (S)- 18 F-fluspidine appears to be the most suitable candidate for S1R PET imaging in human.…”

Bridging from Brain to Tumor Imaging: (S)-(−)- and (R)-(+)-[18F]Fluspidine for Investigation of Sigma-1 Receptors in Tumor-Bearing Mice

“…Our group has recently developed ( R )-(+)- and ( S )-(−)-[ 18 F]fluspidine [ 31 ], two specific radioligands for Sig1R PET with promising preclinical properties and distinctive kinetics [ 33 , 35 ]. In this publication, we investigated the suitability of both enantiomers of [ 18 F]fluspidine to image Sig1R in different mouse tumor models.…”

Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study

“…To clarify pridopidine's mechanism of action, we used PET imaging to assess the receptor occupancy of pridopidine at previously used clinical doses. (S)-(-)-[ 18 F] Fluspidine (termed here [ 18 F] Fluspidine for simplicity) proved to be a selective and suitable radioligand for neuroimaging of S1R availability in preclinical PET studies and a recent first-in-human PET investigation [19][20][21][22][23]. (S)-(-)-[ 18 F] Fluspidine shows a more favorable metabolic profile compared with its (R)-(-)-enantiomer, and its binding to the S1R is reversible, whereas binding of the (R)-(-)-enantiomer is irreversible [20].…”