Effects of trihexyphenidyl and L-dopa on brain muscarinic cholinergic receptor binding measured by positron emission tomography

Shinotoh, Hitoshi; Asahina, Masato; Ito, Osamu; Suhara, Tetsuya; Hirayama, Keizo; Tateno, Yukio

doi:10.1007/bf02252661

Cited by 13 publications

(5 citation statements)

References 27 publications

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“…Similar occupancy values (mean 28%) were observed in Parkinson patients during treatment with a clinical dose of trihexyphenidyl (4 mg) [32]. In contrast to trihexyphenidyl, L-DOPA had no effect on the measured k3 values of [ 11 C]NMPB.…”

Section: Muscarinic Antagonistssupporting

confidence: 73%

Measuring Receptor Occupancy with PET

Waarde¹

2000

CPD

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Many physiological and biochemical measurements can be performed noninvasively in humans with modern imaging techniques like magnetic resonance imaging (MRI), positron emission tomography (PET) or single-photon emission computed tomography (SPECT). This review focuses on the monitoring of drug-receptor interactions in patients and healthy volunteers with PET. Such studies depend on the availability of a suitable radioligand; they are already possible for classical and atypical neuroleptics, anxiolytics, antidepressants, anticholinergics, antihistamines, antiepileptics, beta-blockers and hypnotic drugs. In Phase I-II human studies, measurements of plasma pharmacokinetics can be combined with images of receptor occupancy and be quantitatively related to pharmacologic effects which are induced in the same subjects. Optimal dosing schedules can be defined and valuable information for the design of Phase III studies can be acquired. Moreover, the effect of interventions (e.g. change of dose, additional medication) can be predicted. Medical imaging techniques will play an increasing role in clinical pharmacology and allow well-informed go/no-go decisions in future drug development.

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Section: Muscarinic Antagonistssupporting

confidence: 73%

Measuring Receptor Occupancy with PET

Waarde¹

2000

CPD

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“…Because previous studies have shown that mAChRs regulate striatal DA release, , Threlfell et al 2010, Threlfell & Cragg 2011 we tested the hypothesis that THP enhances DA release by performing FSCV in dorsolateral striatum while bath applying 3-300 nM THP. This dose range was selected based on the affinities of THP for mAChRs (2-20 nM depending on the mAChR subtype (Bolden et al 1992)), and on known THP receptor occupancy in humans, (Shinotoh et al 1994) which suggests that THP concentrations in brain are near-saturating for all mAChRs subtypes at the high doses used for the treatment of dystonia. A concentration of 300 nM THP achieves ~97-99% mAChR occupancy.…”

Section: Trihexyphenidyl Enhances Da Releasementioning

confidence: 99%

Trihexyphenidyl rescues the deficit in dopamine neurotransmission in a mouse model of DYT1 dystonia

Downs

Fan

Donsante

et al. 2019

Neurobiology of Disease

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Trihexyphenidyl, a nonselective muscarinic receptor antagonist, is the small molecule drug of choice for the treatment of DYT1 dystonia, but it is poorly tolerated due to significant side effects. A better understanding of the mechanism of action of trihexyphenidyl is needed for the development of improved treatments. Because DTY1 dystonia is associated with both abnormal cholinergic neurotransmission and abnormal dopamine regulation, we tested the hypothesis that trihexyphenidyl normalizes striatal dopamine release in a mouse model of DYT1 dystonia using ex vivo fast scan cyclic voltammetry and in vivo microdialysis. Trihexyphenidyl increased striatal dopamine release and efflux as assessed by ex vivo voltammetry and in vivo microdialysis respectively. In contrast, ʟ-DOPA, which is not usually effective for the treatment of DYT1 dystonia, did not increase dopamine release in either Dyt1 or control mice. Trihexyphenidyl was less effective at enhancing dopamine release in Dyt1 mice relative to controls ex vivo (mean increase WT: 65% vs Dyt1: 35%). Trihexyphenidyl required nicotinic receptors but not glutamate receptors to increase dopamine release. Dyt1 mice were more sensitive to the dopamine release decreasing effects of nicotinic acetylcholine receptor antagonism (IC 50 : WT= 29.46nM, Dyt1= 12.26nM) and less sensitive to acetylcholinesterase inhibitors suggesting that nicotinic acetylcholine receptor neurotransmission is altered in Dyt1 mice, that nicotinic receptors indirectly mediate the differential effects of trihexyphenidyl in Dyt1 mice, and that nicotinic receptors may be suitable therapeutic targets for DYT1 dystonia.

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“…The endogenous O -[2- 11 C]acetyl- l -carnitine functions as an acetyl group transporter, acting in the inner mitochondria membrane. It is of great interest in PET studies of, for example, the pathways of the tricarboxylic acid (TCA) cycle. , N -[ 11 C]Methylpiperidyl benzilate is a muscarinic antagonist and has been used in PET studies of the cholinergic system …”

Section: Resultsmentioning

confidence: 99%

Supercritical Fluid Extraction of ¹¹C-Labeled Metabolites in Tissue Using Supercritical Ammonia

Jacobson

Moulder

et al. 1997

Anal. Chem.

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Supercritical fluid extraction (SFE) of 11C-labeled tracer compounds and their metabolites from biological tissue was performed using supercritical ammonia in an attempt to develop a rapid extraction procedure that allowed subsequent analysis of the labeled metabolites. Metabolites were extracted from kidneys and brain in rats given in vivo injections of the radiotracers O-[2-11C]acetyl-L-carnitine and N-[11C]methylpiperidyl benzilate, respectively. Only a minimal sample pretreatment of the tissue was necessary, i.e., cutting into 10-20 pieces and mixing with the drying agent Hydromatrix, before it was loaded into the extraction vessel. Extraction efficiency was measured for SFE at temperatures over the range of 70-150 degrees C and a pressure of 400 bar. For O-[2-11C]acetyl-L-carnitine, 66% of the radioactivity was trapped in the collected fractions and 12% remained in the extraction vessel. For the more lipophilic N-[11C]methylpiperidyl benzilate, 93% of the activity was collected and less than 1% remained in the extraction vessel. Labeled metabolites were analyzed by LC and also, in the case, of O-[2-11C]acetyl-L-carnitine by LC/MS. The complete extraction procedure, from removal of the biological tissue until an extract was ready for analysis, was 25 min, corresponding to about one half-life of the radionuclide 11C.

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Effects of trihexyphenidyl and L-dopa on brain muscarinic cholinergic receptor binding measured by positron emission tomography

Cited by 13 publications

References 27 publications

Measuring Receptor Occupancy with PET

Measuring Receptor Occupancy with PET

Trihexyphenidyl rescues the deficit in dopamine neurotransmission in a mouse model of DYT1 dystonia

Supercritical Fluid Extraction of ¹¹C-Labeled Metabolites in Tissue Using Supercritical Ammonia

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Effects of trihexyphenidyl and L-dopa on brain muscarinic cholinergic receptor binding measured by positron emission tomography

Cited by 13 publications

References 27 publications

Measuring Receptor Occupancy with PET

Measuring Receptor Occupancy with PET

Trihexyphenidyl rescues the deficit in dopamine neurotransmission in a mouse model of DYT1 dystonia

Supercritical Fluid Extraction of 11C-Labeled Metabolites in Tissue Using Supercritical Ammonia

Contact Info

Product

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Supercritical Fluid Extraction of ¹¹C-Labeled Metabolites in Tissue Using Supercritical Ammonia