Kim A. Bergström

Single-photon emission tomography imaging of monoamine transporters in impulsive violent behaviour

Abstract.Several studies have shown that impulsive violent and suicidal behaviour is associated with a central serotonin deficit, but until now it has not been possible to use laboratory tests with high sensitivity and specificity to study this kind of deficit or to localize the sites of serotonergic abnormalities in the living human brain. The aim of this study was to test the hypothesis that monoamine transporter density in brain is decreased in subjects with impulsive violent behaviour. We studied serotonin (5-HT) and dopamine (DA) transporter specific binding in 52 subjects (21 impulsive violent offenders, 21 age- and sex-matched healthy controls, and ten non-violent alcoholic controls) with single-photon emission tomography (SPET) using iodine-123-labelled 2β-carbomethoxy-3β(4-iodophenyl)tropane ([123I]β-CIT) as the tracer. The blind quantitative analysis revealed that the 5-HT specific binding of [123I]β-CIT in the midbrain of violent offenders was lower than that in the healthy control subjects (P<0.005; t test) or the non-violent alcoholics (P<0.05). The results imply that habitual impulsive aggressive behaviour in man is associated with a decrease in the 5-HT transporter density.

Reduced serotonin transporter binding in binge eating women

Abstract. Rationale: There is evidence that abnormalities in brain dopamine, norepinephrine and serotonin metabolism may play an important role in binge eating. Serotonin-active antidepressant drugs have also been found to decrease binge eating. Objective: We investigated serotonin transporter binding in obese binge-eating women. Eleven obese binge-eating and seven obese control women participated in the study. The subjects were not taking any medication known to affect serotonin (5-HT) transporters. Methods: We used single-photon emission tomography (SPECT) with the radioligand 123I-labelled nor-β-CIT, which specifically labels 5-HT transporters. Results: Obese binge-eating women showed significantly decreased 5-HT transporter binding in the mid-brain compared with obese controls (2.1±0.5 versus 2.9±0.5, respectively). Conclusions: SPECT imaging with a ligand specific for 5-HT transporters can be used to assess altered serotonin transporter binding in the living human brain. The results tentatively suggest that 5-HT transporter binding is decreased in binge-eating women.

Dopamine transporter and D2-receptor density in late-onset alcoholism

Abstract Rationale: Late onset type 1 alcoholism has been suggested to be associated with an underlying dopaminergic defect. Therefore, it is relevant to study both postsynaptic D2-receptor and presynaptic dopamine transporter (DAT) densities among alcoholics. Objective: We investigated DAT densities, along with striatal and extrastriatal dopamine D2-receptor densities, in nine non-violent late-onset male alcoholics, who had no major mental disorder nor antisocial personality disorder (ASPD), and nine healthy controls. Methods: [123I]PE2I and [123I]epidepride were used in SPECT imaging. Results: DAT occupancy ratios (striatum/cerebellum) were significantly lower among alcoholics than in controls. Extrastriatal D2-receptor occupancy ratios (temporal pole/cerebellum) were not significantly different between the groups. Conclusions: Striatal presynaptic DAT densities are decreased among type 1 alcoholics, and this finding is not associated with recent alcohol abuse.

Comparison of iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane and 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane for imaging of the dopamine transporter in the living human brain

Several cocaine congeners are of potential for imaging the dopamine transporter (DAT). Previous studies have shown that iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane ([123I]β-CIT) is a promising radiotracer for imaging the serotonin (5-HT) and dopamine (DA) transporters in the living human brain with single-photon emission tomography (SPET). [123I]β-CIT was found to be not very practical for 1-day DAT imaging protocols since peak DAT uptake occurs later than 8 h. Here we report a pilot comparison of [123I]β-CIT and 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane ([123I]β-CIT FP), using SPET imaging in four healthy male subjects. Peak uptake of [123I]β-CIT-FP into the basal ganglia occurred earlier (3–4 h after injection of tracer) than that of [123I]β-CIT (>8 h). However, the specific DAT binding of [123I]β-CIT-FP in the basal ganglia was somewhat less (0.813±0.047) than that of [123I]β-CIT (0.922±0.004). Imaging quality is excellent with both tracers and they are potentially of value for brain imaging in various neuropsychiatric disorders.

Striatal dopamine transporter in different disability stages of Parkinson's disease studied with [123I]β-CIT SPECT

Six healthy controls and eighteen patients with Parkinsons disease in different disability stages were studied with SPECT using [(123)I]beta-CIT to label the striatal dopamine transporter. The mean uptake of [(123)I]beta-CIT in the putamen was reduced to 54% of the control mean and to 65% of the average control value in the caudate nucleus. In patients with totally, or predominantly unilateral symptoms the reduction was greater on the side opposite to the predominant symptoms (to 56% of the control mean in the contralateral putamen and to 77% in the ipsilateral putamen). There was a significant negative correlation between [(123)I]beta-CIT uptake in the putamen and the Hoehn and Yahr stage (r = -0.81, p < 0.0001). An analysis of covariance was performed using age and disease duration as covarianes, and the correlation between putaminal [(123)I]beta-CIT uptake and parkinsonian disability according to the Hoehn and Yahr stage remained significant (r = -0.75, p = 0.02). A similar correlation was seen in the caudate nucleus (r = -0.79, p < 0.0001) between the uptake of [(123)I]beta-CIT and the Hoehn and Yahr stage. The correlation also remained significant after correction for the duration of disease and age of the patients (r= -0.76, p = 0.02). The present results show that [1231],Q-CIT SPECT is a useful method to study the function of presynaptic dopaminergic terminals in PD, and might be used in the early diagnosis and follow-up of the disease.

Dopamine D2 receptors and transporters in type 1 and 2 alcoholics measured with human whole hemisphere autoradiography

Increasing evidence implies the involvement of the dopamine (DA) system in the pathogenesis of alcoholism. We measured striatal DA D2 receptors in Cloninger type 1 and 2 alcoholics by using [125I]epidepride in human postmortem whole hemispheric autoradiography (WHA), which provides high‐resolution images corresponding to positron emission tomographic (PET) studies. We also evaluated the correlation between transporter and receptor DA binding site densities and putative correlation of [125I]epidepride binding between the dorsal striatum and nucleus accumbens. In the type 1 alcoholics, the DA D2 receptor density was 21.4–32.6% lower in all dorsal striatal structures (caudate, putamen, globus pallidus) when compared with the controls. Type 2 alcoholics had 19.6–21.4% lower binding in other dorsal striatal structures, except medial globus pallidus, where they were not significantly different from controls. The density of DA D2 receptors and DAT had a significant positive correlation only in the putamen of type 1 alcoholics. The binding of [125I]epidepride showed also consistent and statistically significant positive correlation between nucleus accumbens and all dorsal striatal areas in type 1 alcoholics but not in the controls. In the type 2 alcoholics, the correlation was weaker than that observed in the type 1 alcoholics, and no correlation was observed between nucleus accumbens and globus pallidus. Our results show that these two subgroups of alcoholics have stark differences in their DA D2 receptor binding characteristics. Type 2 alcoholics may have selective deficiency in the dorsal striatum, whereas in limbic structures they may not differ significantly from controls. Moreover, WHA provides a useful tool for detailed mapping of neuronal receptors in healthy as well as diseased brain, and can also be used in radioligand development for PET. Hum. Brain Mapp. 20:91–102, 2003.

SPECT/CT imaging of radiolabeled cubosomes and hexosomes for potential theranostic applications

We have developed a highly efficient method for the radiolabeling of phytantriol (PHYT)/oleic acid (OA)-based hexosomes based on the surface chelation of technetium-99m ((99m)Tc) to preformed hexosomes using the polyamine 1, 12-diamino-3, 6, 9-triazododecane (SpmTrien) as chelating agent. We also report on the unsuccessful labeling of cubosomes using the well-known chelating agent hexamethylpropyleneamine oxime (HMPAO). The (99m)Tc-labeled SpmTrien-hexosomes ((99m)Tc-SpmTrien-hexosomes) were synthesized with good radiolabeling (84%) and high radiochemical purity (>90%). The effect of radiolabeling on the internal nanostructure and the overall size of these aqueous dispersions was investigated by using synchrotron small angle X-ray scattering (SAXS), dynamic light scattering (DLS), and transmission electron cryo microscopy (cryo-TEM). Further, we show the utility of (99m)Tc-SpmTrien-hexosomes for the in vivo imaging of healthy mice using single photon emission computed tomography (SPECT) in combination with computed tomography (CT), i.e. SPECT/CT. SPECT/CT experiments of subcutaneously administered (99m)Tc-SpmTrien-hexosomes to the flank of mice showed a high stability in vivo allowing imaging of the distribution of the radiolabeled hexosomes for up to 24 h. These injected (99m)Tc-SpmTrien-hexosomes formed a deposit within the subcutaneous adipose tissue, displaying a high biodistribution of ≈ 343% injected dose/g tissue (%ID/g), with negligible uptake in other organs and tissues. The developed (99m)Tc labeling method for PHYT/OA-based hexosomes could further serve as a useful tool for investigating and imaging the in vivo performance of cubosomal and hexosomal drug nanocarriers.

Abnormal structure of human striatal dopamine re-uptake sites in habitually violent alcoholic offenders: a fractal analysis

Both animal and human studies imply that aggressive behaviour is associated with increased dopaminergic transmission. Our hypothesis was that impulsive violent offenders have also higher heterogeneity of the striatal dopamine transporter (DAT) density than controls. We performed a fractal analysis in 21 impulsive violent offenders, 10 non-violent alcoholics and 21 controls to measure the heterogeneity and laterality of the striatal DAT density characterised by [123I]beta-CIT single-photon emission tomography (SPET). The [123I]beta-CIT distribution was significantly more heterogeneous in the right striatum of violent offenders than in healthy controls. In addition, in young violent offenders there was no normal left-to-right asymmetry observed in control subjects of the same age. The normalisation of the left-to-right asymmetry may reflect late neurobiological maturation.

The dosimetry of iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane

This report documents the radiation dosimetry of iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane [123I]β-CIT in humans. The mean absorbed doses for various organs and the effective dose equivalent were estimated from whole-body scans, blood samples and single-photon emission tomography scans acquired up to 22 h after the injection of a known amount of tracer. The basal ganglia, the liver and the lower large intestinal wall received the highest mean absorbed doses of 0.270 mGy/MBq, 0.038 mGy/MBq and 0.034 mGy/MBq, respectively. The effective dose equivalent for adults was estimated using 11 organs and the ICRP-87 radiation dose model and was 0.031 mSv/MBq. The radiation dose to the basal ganglia limits the maximum injected activity of [123I]β-CIT to 185 MBq for a single study.

Pre-Targeting and Direct Immunotargeting of Liposomal Drug Carriers to Ovarian Carcinoma

Background Epidermal growth factor receptor (EGFR) is overexpressed in many solid tumor types, such as ovarian carcinoma. Immunoliposome based drug targeting has shown promising results in drug delivery to the tumors. However, the ratio of tumor-to-normal tissue concentrations should be increased to minimize the adverse effects of cytostatic drugs. Methodology/Principal Findings We studied the EGFR-targeted doxorubicin immunoliposomes using pre-targeting and local intraperitoneal (i.p.) administration of the liposomes. This approach was used to increase drug delivery to tumors as compared to direct intravenous (i.v.) administration of liposomes. EGFR antibodies were attached on the surface of PEG coated liposomes using biotin-neutravidin binding. Receptor mediated cellular uptake and cytotoxic efficacy of EGFR-targeted liposomes were investigated in human ovarian adenocarcinoma (SKOV-3 and SKOV3.ip1) cells. In vivo distribution of the liposomes in mice was explored using direct and pre-targeting approaches and SPECT/CT imaging. Targeted liposomes showed efficient and specific receptor-mediated binding to ovarian carcinoma cells in vitro, but the difference in cytotoxicity between targeted and non-targeted liposomes remained small. The relatively low cytotoxic efficacy is probably due to insufficient doxorubicin release from the liposomes rather than lack of target binding. Tumor uptake of targeted liposomes in vivo was comparable to that of non-targeted liposomes after both direct and pre-targeting administration. For both EGFR-targeted and non-targeted liposomes, the i.p. administration increased liposome accumulation to the tumors compared to i.v. injections. Conclusions/Significance Intraperitoneal administration of liposomes may be a beneficial approach to treat the tumors in the abdominal cavity. The i.p. pre-targeting method warrants further studies as a potential approach in cancer therapy.