Brain Regional alpha-[11C]methyl-L-tryptophan trapping in impulsive subjects with borderline personality disorder.

OBJECTIVE: Neurotransmission of serotonin (or 5-hydroxytryptamine [5-HT]) is thought to be disturbed in patients exhibiting impulsive behaviors. However, until recently it has not been possible to test this hypothesis in the brains of living humans. METHOD: Unidirectional trapping of the 5-HT precursor analog alpha-[(11)C]methyl-L-tryptophan (alpha-[(11)C]MTrp) has been proposed as an index of 5-HT synthesis capacity. The authors measured brain regional alpha-[(11)C]MTrp trapping with positron emission tomography in medication-free subjects with borderline personality disorder (N=13) and a healthy comparison group (N=11). Impulsivity was assessed by using a laboratory measure of behavioral disinhibition, go/no-go commission errors. RESULTS: Compared to healthy men, the men with borderline personality disorder had significantly lower alpha-[(11)C]MTrp trapping in corticostriatal sites, including the medial frontal gyrus, anterior cingulate gyrus, superior temporal gyrus, and corpus striatum. In the women with borderline personality disorder, significantly lower alpha-[(11)C]MTrp trapping was seen in fewer regions, but in both men and women, negative correlations with impulsivity scores were identified in the medial frontal gyrus, anterior cingulate gyrus, temporal gyrus, and striatum. CONCLUSIONS: Low 5-HT synthesis capacity in corticostriatal pathways may contribute to the development of impulsive behaviors in persons with borderline personality disorder.

Statistical mapping analysis of serotonin synthesis images generated in healthy volunteers using positron-emission tomography and alpha-[11C]methyl-L-tryptophan.

OBJECTIVES: To assess the suitability of analyzing functional images of brain serotonin (5-HT) synthesis with statistical parametric mapping (SPM), and to investigate further possible sex-related regional differences. DESIGN: Prospective study. PARTICIPANTS: Six healthy men and 5 healthy women. INTERVENTION: Participants' brains were scanned with positron-emission tomography (PET) after intravenous injection of alpha-[11C]methyl-L-tryptophan (alpha-[11C]MTrp). OUTCOME MEASURES: Tissue radioactivity images were converted into functional images using the Patlak plot approach, and analyzed with 2 methods for global normalization in the SPM program: proportional scaling and analysis of covariance (ANCOVA). RESULTS: The data structure suggests that PET alpha-[11C]MTrp data meet the criteria for analysis with SPM, and that the proportional scaling method is more appropriate than the ANCOVA method for normalization. Regional differences in 5-HT synthesis were identified between men and women, and the significance of these findings was supported by region of interest (ROI) analyses. CONCLUSION: SPM analyses of PET alpha-[11C]MTrp data may be of value for identifying regional differences in brain 5-HT synthesis between groups, and in investigating the effects of psychotropic drugs. Since we found regional differences between male and female subjects, men and women should not be grouped for data analysis in PET alpha-[11C]MTrp studies.

Stereospecific synthesis of alpha-methylated amino acids.

Both 2,5-trans and 2,5-cis disubstituted 2-tert-butyl-5-(indol-3-yl)methylimidazolidin-4-ones were synthesised and their enolates were prepared using LDA. While the enolate of the 2,5-trans disubstituted derivative could not be methylated, the enolate of the cis-2,5-disubstituted derivative was successfully methylated with methyl iodide to a product which on hydrolysis gave enantiomerically pure alpha-methyl-L-tryptophan.

Acute effects of 3,4-methylenedioxymethamphetamine on brain serotonin synthesis in the dog studied by positron emission tomography.

The influence of an acute dose (2 mg/kg; i.v.; infused over 10 min) of 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) on the brain serotonin synthesis in the dog was assessed using alpha [11C]methyl-L-tryptophan and positron emission tomography. The rate of serotonin synthesis measured 1 h after injection of MDMA was six times greater than the base line (before MDMA) synthesis. Five hours after the MDMA injection, serotonin synthesis was about one half that at the base line, and about one thirteenth of the synthesis at 1 h after MDMA. A large increase seen 1 h after MDMA probably relates to the large release of serotonin by MDMA and reflects an attempt of the serotonergic system to replenish released serotonin. This probably correlates with the mood changes reported by humans after MDMA intake. Decrease observed 5 h after MDMA, in part, probably relates to the inhibitory effects of the released serotonin, which could act on the activity of tryptophan hydroxylase directly or indirectly via other monoaminergic systems (e.g. dopaminergic).

Validation of a less-invasive method for measurement of serotonin synthesis rate with alpha-[11C]methyl-tryptophan.

We tested in normal human subjects a less invasive method to obtain plasma input function required in the calculation of the brain serotonin synthesis rate measured with positron emission tomography (PET) and alpha-[11C]methyl-tryptophan (alpha-MTrp). The synthesis rates derived with the arterial input function were compared to those derived from venous plasma and venous sinus time-radioactivity curves obtained from dynamic PET images. Dynamic PET images were obtained for the lengths up to 90 minutes after an injection of alpha-MTrp (400 to 800 MBq). Input functions were generated from both artery and vein in three subjects, and from artery only in two subjects. Net unidirectional uptake constants of alpha-MTrp (K*; mL/g/min) were calculated in several brain regions graphically using data between 20 and 60 minutes after injection with different input functions. In the five subjects with arterial sampling, we tested two methods for correcting the input functions from the venous samples: (1) normalization to the mean exposure time at 20 minutes from arterial curve; and (2) the use of the venous sinus curve for the first 20 minutes. Venous curves coincided with the arterial ones after about 20 minutes. When the venous curves were used, there was an underestimation of the area under the curves up to 20 minutes, resulting in a 5% to 30% overestimation of K* values. Combined use of the sinus curve up to 20 minutes and venous curve from 20 to 60 minutes as an input function resulted in the K* (mL/g/min) values larger by 7.1 +/- 3.8% than the K* values estimated with the arterial input function. Normalization of the venous curve to the exposure time at 20 minutes obtained from the arterial plasma curve resulted in a bias in the K* of about -0.34 +/- 3.32%. The bias from the K* values was propagated to the serotonin synthesis rates. The use of a combination of the venous blood samples and venous sinus as the input function resulted in an acceptable bias in the serotonin synthesis rates from the tissue time-radioactivity curves generated by PET.

Differences between males and females in rates of serotonin synthesis in human brain.

Rates of serotonin synthesis were measured in the human brain using positron emission tomography. The sensitivity of the method is indicated by the fact that measurements are possible even after a substantial lowering of synthesis induced by acute tryptophan depletion. Unlike serotonin levels in human brain, which vary greatly in different brain areas, rates of synthesis of the indolamine are rather uniform throughout the brain. The mean rate of synthesis in normal males was found to be 52% higher than in normal females; this marked difference may be a factor relevant to the lower incidence of major unipolar depression in males.

Asymmetric radiosynthesis of alpha-[11C]methyl-L-tryptophan for PET studies.

Asymmetric radiosynthesis of alpha-[11C]methyl-L-tryptophan has been achieved using the enantioselective [11C]methylation of the enolate of either 8-(phenylsulfonyl) or 8-acetyl substituted derivatives of dimethyl (2S.3aR, 8aS)-(+)-hexahydropyrrolo[2,3-b]indole-1,2-dicarboxylate. Reaction of the enolates generated by treatment with LDA at -78 degrees C, with [11C]methyl iodide at -78 degrees C gave in 5 min incorporation of the radiolabel of 86% for 8-phenylsulfonyl derivative and 63% for 8-acetyl derivative. The hexahydropyrrolo[2,3-b]indoles were then decyclized to the fully protected alpha-[11]methyl-L-tryptophan by treatment with trifluoroacetic acid. Removal of all the protecting groups, including the phenylsulfonyl, was achieved by reaction with 10 N NaOH at 210 degrees C in a sealed vial. Neutralization of the alkali with 10 N H2SO4 followed by purification by HPLC gave alpha-[11C]methyl-L-tryptophan with an overall radiochemical yield of 20% (uncorrected for decay) relative to the amounts of [11C]CH3I from 8-phenylsulfonyl derivative, and 9% (relative to [11C]CH3I; uncorrected for decay) from 8-acetyl derivative in a preparation time of 40 min after [11C]methyl iodide was introduced into the reaction mixture.

Synthesis of enantiomerically pure alpha-[14C]methyl-L-tryptophan.

A practical method for the preparation of large amounts of enantiomerically pure alpha-[14C]methyl-L-tryptophan using the enzymatic resolution of the corresponding D,L-methyl ester is reported. The radiolabelled alpha-methyl group was introduced using the alpha-methylation of the lithium enolate of the Schiff base of L-tryptophan methyl ester. Hydrolysis of the Schiff base with 1N HCl provided the D,L-methyl ester of alpha-[14C]methyl tryptophan. Enantioselective enzymatic hydrolysis of the L-methyl ester by alpha-chymotrypsin gave the enantiomerically pure alpha-[14C]methyl-L-tryptophan. The overall yield of this preparation was 33%.