Evaluation of the potassium channel tracer [18F]3F4AP in rhesus macaques.

Demyelination causes slowed or failed neuronal conduction and is a driver of disability in multiple sclerosis and other neurological diseases. Currently, the gold standard for imaging demyelination is MRI, but despite its high spatial resolution and sensitivity to demyelinated lesions, it remains challenging to obtain specific and quantitative measures of molecular changes involved in demyelination. To understand the contribution of demyelination in different diseases and to assess the efficacy of myelin-repair therapies, it is critical to develop new in vivo imaging tools sensitive to changes induced by demyelination. Upon demyelination, axonal K+ channels, normally located underneath the myelin sheath, become exposed and increase in expression, causing impaired conduction. Here, we investigate the properties of the K+ channel PET tracer [18F]3F4AP in primates and its sensitivity to a focal brain injury that occurred three years prior to imaging. [18F]3F4AP exhibited favorable properties for brain imaging including high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics. [18F]3F4AP showed preferential binding in areas of low myelin content as well as in the previously injured area. Sensitivity of [18F]3F4AP for the focal brain injury was higher than [18F]FDG, [11C]PiB, and [11C]PBR28, and compared favorably to currently used MRI methods.

Estimation of noise-free variance to measure heterogeneity.

Variance is a statistical parameter used to characterize heterogeneity or variability in data sets. However, measurements commonly include noise, as random errors superimposed to the actual value, which may substantially increase the variance compared to a noise-free data set. Our aim was to develop and validate a method to estimate noise-free spatial heterogeneity of pulmonary perfusion using dynamic positron emission tomography (PET) scans. On theoretical grounds, we demonstrate a linear relationship between the total variance of a data set derived from averages of n multiple measurements, and the reciprocal of n. Using multiple measurements with varying n yields estimates of the linear relationship including the noise-free variance as the constant parameter. In PET images, n is proportional to the number of registered decay events, and the variance of the image is typically normalized by the square of its mean value yielding a coefficient of variation squared (CV(2)). The method was evaluated with a Jaszczak phantom as reference spatial heterogeneity (CV(r)(2)) for comparison with our estimate of noise-free or 'true' heterogeneity (CV(t)(2)). We found that CV(t)(2) was only 5.4% higher than CV(r)2. Additional evaluations were conducted on 38 PET scans of pulmonary perfusion using (13)NN-saline injection. The mean CV(t)(2) was 0.10 (range: 0.03-0.30), while the mean CV(2) including noise was 0.24 (range: 0.10-0.59). CV(t)(2) was in average 41.5% of the CV(2) measured including noise (range: 17.8-71.2%). The reproducibility of CV(t)(2) was evaluated using three repeated PET scans from five subjects. Individual CV(t)(2) were within 16% of each subject's mean and paired t-tests revealed no difference among the results from the three consecutive PET scans. In conclusion, our method provides reliable noise-free estimates of CV(t)(2) in PET scans, and may be useful for similar statistical problems in experimental data.

Pharmacokinetics of 18F-labeled trovafloxacin in normal and Escherichia coli-infected rats and rabbits studied with positron emission tomography.

OBJECTIVE: To measure tissue pharmacokinetics of trovafloxacin (CP 99,219) in normal and infected animals by both direct tissue radioactivity measurements and positron emission tomography (PET). METHODS: Concentrations of [18F]trovafloxacin were measured in normal and infected rats (n=6/group), at 10, 30, 60, and 120 min after injection, by radioactivity measurements. In normal rabbits (n=4) and rabbits with Escherichia coli thigh infection (n=4), tissue concentrations of drug were measured over 2 h with PET. After acquiring the final images, the rabbits were killed and tissue concentrations measured with PET were compared to the results of direct tissue radioactivity measurements. RESULTS: In both species, there was rapid distribution of [18F] trovafloxacin in most peripheral organs. Peak concentrations of more than five times the MIC90 of most Enterobacteriaceae and anaerobes (>100-fold for most organisms) were achieved in all tissues and remained above this level for >2 h. Particularly high peak concentrations were achieved in the kidney (>75 micro g/g), liver (>100 micro g/g), blood (>40 micro g/g), and lung (>10 micro g/g). Even though the concentration of trovafloxacin in infected muscle was reduced (p<0.01), the peak concentration was still >4 micro g/g and tissue levels remained above 2 micro g/g for more than 2 h. Due to the lower concentrations that were achieved in the brain (peak approximately 5 micro g/g), it is expected that trovafloxacin will have limited central nervous system toxicity. CONCLUSION: PET with [18F]trovafloxacin is a useful technique for non-invasive measurements of tissue pharmacokinetics.