Search

BACKGROUND: Corticomotor excitability has been shown to correlate with motor learning and functional recovery. The aim of the present study was to monitor changes in excitability of the corticomotor pathways induced by neck training and to compare the effects in patients with neck or knee pain and pain-free participants.METHODS: Corticomotor excitability was assessed using transcranial magnetic stimulation and electromyography at baseline, after 30 min and 1 h, and at a 1-week follow-up visit. The primary outcome measures were changes in amplitudes and latencies of motor evoked potentials (MEPs) at 1-week follow-up.RESULTS: MEP responses induced by neck training yielded significantly different outcomes in the three groups. In the group with neck pain and training, MEP amplitudes were significantly reduced between baseline and 30 min (p ≤ 0.05), but with no significant difference between baseline, 1 h (p = 0.178) and 1 week (p = 0.067). In the group with knee pain and training, MEP amplitudes significantly increased between baseline and 30 min (p ≤ 0.01) and 1 h (p CONCLUSION: Neck training reduced neuroplastic responsiveness of corticomotor pathways in neck pain patients in contrast to knee pain patients and pain-free participants. Increased attention to adaptive and maladaptive neuroplastic responses induced by training may prove valuable in the process of optimizing clinical outcomes.

Der Erfindung liegt die Aufgabe zugrunde, diese Nachteile zu überwinden und ein schnelles, reproduzierbares Herstellungsverfahren für chemisch und radiochemisch reine 16a- [18F]Fluorestradiolsulfamate, die wahlweise in 3-oder 17-Stellung monosulfamoyliert bzw. in 3, 17-Stellung disulfamoyliert worden sind, vorzustellen. Die Synthese kann, ausgehend von den 16,17-O-Sulfuryl-16-epiestriolderivaten, ohne Zwischenisolierung der intermediär anfallenden 16a-[18F]Fluorestradiolderivate in eigens für die Markierung vorgesehenen käuflichen Modulen mittels computergestützter Programme durchgeführt werden. Dadurch wird die Kontaminierungsgefahr mit radioaktivem Material auf ein Mindestmaß reduziert.

16alpha-Fluoroestradiol-3,17beta-disulfamate (FESDS) strongly inhibits estrone sulfatase (ES), an enzyme which is also present in the brain. The enzyme is probably involved in important regulatory functions of neurosteroids which may be disturbed in certain brain diseases. In the present study [18F]FESDS was used to measure the amount of ES in various rat brain regions using quantitative in vitro autoradiography. The obtained values vary between 0.29 pmol (mg protein)-1 (pons) and 11.5 pmol (mg protein)-1 (striatum). They are positively correlated with the enzyme activity measured in homogenates of the corresponding regions. Because this radiotracer binds also to carbonic anhydrase in the brain it is only limited use for in vivo imaging studies.

Based on a high affinity to the enzyme estrone sulfatase (ES) 16alpha-[18F]fluoroestradiol-3,17beta-disulfamate ([18F]FESDS) has been suggested as a potential PET tracer for imaging steroid-dependent breast tumours. The distribution of [18F]FESDS was studied in rats, tumour-bearing nude mice and piglets. In all species evidence for tracer binding to a second target, the enzyme carbonic anhydrase (CA), was obtained. ES and CA inhibitors significantly reduced the radiotracer uptake in various organs but not in tumours. It is concluded that [18F]FESDS binds to ES and CA in vivo but this binding is not strong enough to allow tumour imaging with positron emission tomography (PET)..

After successful synthesizing 16alpha-[18F]fluoroestradiol-3,17beta-disulphamate in an automatic procedure, we studied the conditions for obtaining 16alpha- [18F]fluoroestradiol-mono-sulphamates in a similar manner. The described procedure can simultaneously provide approximately 3 GBq of 16alpha-[18F]fluoroestradiol-3-sulphamate and 1 GBq of 16alpha-[18F]fluoroestradiol-17beta-sulphamate of high radiochemical purity. By treating 16alpha-[18F]fluoroestradiol-3,17beta-disulphamate with Kryptofix 2.2.2 and potassium carbonate, 16alpha-[18F]fluoroestradiol-17beta-sulphamate also becomes available at high radioactivity.

16-Alpha-[18F]Fluoroestradiol-3,17-Beta-disulphamate ([18F]FESDS) has recently been discovered to display affinity to carbonic anhydrase (CA) and estrone sulfatase (ES), enzymes which are expressed in the CNS and suggested to play a regulatory role in various brain diseases. In this study the radioligand was used to provide quantitative data on the regional distribution of these enzymes in the rat brain. The expression of CA I, CA II and ES has been studied in rat brain regions with RT-PCR. CA II and ES but not CA I has been detected in all regions. About 80-90 % of the total binding of [18F]FESDS to brain slices represents binding to CA (displaceable with acetazolamide). Binding of [18F]FESDS to ES was studied with selective inhibition of CA using acetazolamide. Bmax values of between 0.3 pmol/mg (pons) and 11.5 pmol/mg (striatum) were obtained in various brain regions. The Kd and Bmax values of ES binding were used as constants to calculate Kd and Bmax of CA binding from inhibition studies with FESDS. Bmax values of between 6.2 pmol/mg protein (striatum) and 14.6 pmol/mg (cerebellum) were obtained. The Kd-values varied between 33 nM and 166 nM, which is similar to the Kd of [18F]FESDS binding to purified human CA-II (54 nM). The affinity of FESDS to ES is lower by about factor 5. Furthermore, the enzymatic activity of ES in six rat brain regions was determined and found to be correlated to the corresponding [18F]FESDS binding. It is concluded, that [18F]FESDS can be used for mapping of CA and ES in vitro. The in vivo use of the radioligand may be limited because of its bipolar binding profile.

After 16alpha-[18F]fluoroestradiol ([18F]FES) has been successfully prepared in an automated module, the synthesis of 16alpha-[18F]fluoroestradiol-3,17beta-disulphamate ([18F]FESDS) is described as a module-assisted one-pot procedure which can provide 10 GBq [18F]FESDS with a radiochemical purity better than 99 %. The procedure is reliable and reproducible and requires a time of about 90 min. Because of its high sulphatase-inhibitory effect [18F]FESDS is thought to be a new PET tracer to image sites of high sulphatase activity.

16alpha-Fluoroestradiol-3,17beta-disulphamate has proven to be a very strong sulphatase inhibitor. Because the sulphatase activity is high in breast cancer tissue there was much hope to image human mammary tumours by using 16alpha-[18F]fluoroestradiol-3,17beta-disulphamate ([18F]FESDS) in PET investigations. For biological characterizing, the new radiotracer had to be made available in high specific activity and in radiochemically pure form. Thus, the module-assisted procedure was developed. The synthesis of [18F]FESDS consists of two steps. In a first step, 3-methoxymethyloxy-16beta,17beta- sulphuryldioxy-estra-1,3,5(10)-triene (1) reacted with n.c.a. [18F]fluoride. The labelled product was deprotected by acid hydrolysis to give 16alpha-[18F]fluoroestradiol ([18F]FES). In a second step, [18F]FES was sulphamoylated to [18F]FESDS by using sulphamoyl chloride in presence of equivalent amounts of Kryptofix 2.2.2 and potassium carbonate. HPLC purification allowed to obtain pure [18F]FESDS. The synthesis shown in Figure 1 can be carried out in an automated module as a one-pot procedure. Results: The synthesis required about 90 min from end of bombardment to the final [18F]FESDS ready for use. The time was composed of the time of synthesis (60 min) and the time of column purification (about 30 min). The decay-corrected yield of [18F]FESDS was 22 - 26%. The chemical and radiochemical purity was better than 98%. The specific radioactivity was found to be between 250 and 450 GBq/µmol. When starting with 70 GBq n.c.a. [18F]fluoride, about 8 - 10 GBq [18F]FESDS can be produced. A typical radiochromatogram of the HPLC purification is shown in Fig. 2.

Estradiols are able to form two monosulphamates and one disulphamate. In the present work all the sulphamates of 17alpha-estradiol, 17beta-estradiol and 16alpha-fluoroestradiol were synthesized and characterized. For characterization NMR spectroscopy was used first of all. Because of its high sulphatase inhibitory efficiency and 16alpha-fluoroestradiol-3,17beta-disulphamate found a special interest among the new sulphamates. Just the binding between sulphamate and sulphatase favoured 16alpha-[18F]fluorestradiol-3,17beta-disulphamate to a new radiopharmaceutical which should be appropriate to image the active sites of sulphatase by positron emission tomography. The preparation of 16alpha[18F]fluoroestradiol-3,17beta-disulphamate requires a simple and rapid procedure. The conditions for such a procedure were also elaborated using non-radioactive substances.