Practical benefit of [123I]FP-CIT SPET in the demonstration of the dopaminergic deficit in Parkinson's disease

Loss of striatal dopamine (DA) transporters in Parkinson's disease (PD) has been accurately assessed in vivo by single-photon emission tomography (SPET) studies using [¹²³I]-CIT. However, these studies have also shown that adequate imaging of the striatal DA transporter content can be performed only 20–30 h following the injection of [¹²³I]-CIT, which is not convenient for routine out-patient evaluations. Recently, a new ligand,N--fluoropropyl-2-carbomethoxy-3-(4-iodophenyl)tropane (FP-CIT), became available for in vivo imaging of the DA transporter. The faster kinetics of [¹²³I]FP-CIT have been shown to allow adequate acquisition as early as 3 h following injection. In the present study, loss of striatal DA transporters in five non-medicated PD patients was assessed on two consecutive SPET scans, one with [¹²³I]-CIT (24 h following injection) and one with [¹²³I]FP-CIT (3 h following injection). The ratios of specific to non-specific [¹²³I]FP-CIT uptake in the caudate nucleus and putamen were consistently 2.5-fold lower than those of [¹²³I]-CIT. However, when the uptake ratio of both ligands in these brain regions of patients was expressed as a percentage of the uptake ratio found in healthy controls, both the decrease and the variation of the data were similar. It is concluded on the basis of these findings that [¹²³I]FP-CIT seems as good as [¹²³I]-CIT for the assessment of the dopaminergic deficit in PD. The faster kinetics of [¹²³I]FP-CIT are a clear advantage.     

[123I]Iodobenzamide binding to the rat dopamine D2 receptor in competition with haloperidol and endogenous dopamine—an in vivo imaging study with a dedicated small animal SPECT

Purpose This study assessed [¹²³I]iodobenzamide binding to the rat dopamine D₂ receptor in competition with haloperidol and endogenous dopamine using a high-resolution small animal SPECT.Methods Subsequent to baseline quantifications of D₂ receptor binding, imaging studies were performed on the same animals after pre-treatment with haloperidol and methylphenidate, which block D₂ receptors and dopamine transporters, respectively.Results Striatal baseline equilibrium ratios (V₃) of [¹²³I]iodobenzamide binding were 1.42±0.31 (mean±SD). After pre-treatment with haloperidol and methylphenidate, V₃ values decreased to 0.54±0.46 (p<0.0001) and 0.98±0.48 (p=0.009), respectively.Conclusion The decrease in [¹²³I]iodobenzamide binding induced by pre-treatment with haloperidol reflects D₂ receptor blockade, whereas the decrease in receptor binding induced by pre-treatment with methylphenidate can be interpreted in terms of competition between [¹²³I]IBZM and endogenous dopamine. Findings show that multiple in vivo measurements of [¹²³I]iodobenzamide binding to D₂ receptors in competition with exogenous and endogenous ligands are feasible in the same animal. This may be of future relevance for the in vivo evaluation of novel radioligands as well as for studying the interrelations between pre- and/or postsynaptic radioligand binding and different levels of endogenous dopamine.     

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 2-carbomethoxy-3-(4-iodophenyl)tropane ([¹²³I]-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]-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]-CIT and 2-carbomethoxy-3-(4-iodophenyl)-N-(3-fluoropropyl)nortropane ([¹²³I]-CIT FP), using SPET imaging in four healthy male subjects. Peak uptake of [¹²³I]-CIT-FP into the basal ganglia occurred earlier (3–4 h after injection of tracer) than that of [¹²³I]-CIT (>8 h). However, the specific DAT binding of [¹²³I]-CIT-FP in the basal ganglia was somewhat less (0.813±0.047) than that of [¹²³I]-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.     

Differential kinetics of [123I]β-CIT binding to dopamine and serotonin transporters

Iodine-123-labelled 3-(4-iodophenyl)tropane-2-carboxylic acid ([¹²³I]-CIT) labels both the dopamine transporter (DAT) and the serotonin transporter (5-HTT) and this ligand is able to clarify pathological changes in both dopaminergic and serotonergic systems. However, the differential kinetics of -CIT binding to DAT and 5-HTT has not been clarified fully. In this study we examined time-activity curves of [¹²³I]-CIT in individual regions in the rat brain. Using cerebellum as the reference region,k ₃ andk ₄ values were estimated by a two-compartment kinetic analysis. In the striatum, the kinetics was slowest among all brain areas. In this area specific binding reached its peak 4 h after the injection. In the hypothalamus, specific binding reached its peak 1 h after the injection and its amount did not change until 4 h after the injection. In the occipital cortex, the binding and washout of the ligand were fastest among all brain regions. Estimatedk ₃ values were 0.040±0.003 in the striatum, 0.019±0.002 in the hypothalamus and 0.082±0.011 in the occipital cortex (min^–t, mean ±SD). Estimatedk ₄ values were 0.0034±0.0005 in the striatum, 0.0071±0.0009 in the hypothalamus and 0.083±0.013 in the occipital cortex (min^–1, mean ±SD). Therefore binding kinetics of [¹²³I]-CIT in the region rich in DAT is apparently different from that in the region rich in 5-HTT. These results will provide fundamental data to image both DAT and 5-HTT in one series of examinations with [¹²³I]-CIT.     

Comparison of [123I]ß-CIT and [123I]IPCIT as single-photon emission tomography radiotracers for the dopamine transporter in nonhuman primates

Single-photon emission tomographic (SPET) imaging with the radiotracer [¹²³I]2-carbomethoxy-3-(4-iodophenyl)tropane ([¹²³I]-CIT) has been reported to be a useful in vivo measure of dopamine (DA) transporters. However, in addition to its high DA transporter affinity,-CIT also binds with high affinity to serotonin (5-HT) transporters. 2-Carboisopropoxy-3-(4-iodophenyl)tropane (IPCIT) has been demonstrated by in vitro studies to have higher selectivity for the DA transporter. We compared [¹²³I]-CIT and [¹²³I]IPCIT SPET imaging and plasma metabolite analyses in baboons to evaluate the potential advantages of [¹²³I]IPCIT for quantitative in vivo measurements of DA transporter densities. Both tracers had low levels (2% of total plasma¹²³I activity) of lipophilic radiolabeled metabolites at 420 min. [¹²³I]IPCIT had significantly higher binding to plasma proteins. The average percent free (nonprotein bound) [¹²³I]-CIT and [¹²³I]IPCIT were 52%±7% and 14%±6%, respectively. Region of interest uptake data were normalized by injected dose and body weight. Consistent with the high density of 5-HT transporters in the midbrain and the lower 5-HT transporter affinity of IPCIT, the normalized peak specific midbrain uptake of [¹²³I]-CIT (1.7±0.5) was higher than that of [¹²³I]IPCIT (0.4±0.2). Consistent with its greater lipophilicity, [¹²³I]IPCIT had higher nonspecific uptake, such that normalized cerebellar uptake of [¹²³I]IPCIT was about twice that of [¹²³I]-CIT. The ratio of specific to nonspecific uptake in striatum was greater for [¹²³I]-CIT compared to [¹²³I]IPCIT; however, striatal binding potentials and distribution volumes were not significantly different. In conclusion, [¹²³I]IPCIT demonstrated in vivo a higher DA transporter selectivity and higher level of nonspecific uptake.     

Enhancement of [123I]β-CIT binding in the striatum with clomipramine: Is there a serotonin-dopamine interaction?

Many reports support the concept of serotonergic-dopaminergic interaction in the brain. However, at present, there are few methods to study this relationship in vivo. The purpose of this study was to investigate the effect of serotonin (5-HT) uptake inhibitor, clomipramine, on a dopamine (DA) transporter ligand, [¹²³I]-CIT (RTI-55), in rat brain. Dose-dependent changes in [¹²³I]-CIT specific binding induced by clomipramine were studied in the striatum (rich in DA transporter) and the hypothalamus (rich in 5-HT transporter). The changes in the time-activity curves of [¹²³I]-CIT specific binding after clomipramine injection were also examined in these two regions. Using the cerebellum as the reference region,k ₃ andk ₄ values with and without clomipramine administration were estimated by a two-compartment kinetic analysis. Clomipramine inhibited [¹²³I]-CIT specific binding in the hypothalamus, but enhanced its specific binding in the striatum in a dose-dependent manner. Kinetic analysis showed thatk ₃ in the striatum was increased by 55%. In conclusion, enhancement of [¹²³I]-CIT binding in the striatum after clomipramine administration indicated the possibility of 5-HT-DA interaction.     

Imaging of serotonin and dopamine transporters in the living human brain

Alterations in brain serotonin (5-HT) and dopamine (DA) activity are associated with several neuropsychiatric disorders, but until now it has not been possible to simultaneously visualize or quantify the 5-HT and the DA transporter density in the living human brain. In this paper we report on the imaging of 5-HT and DA transporters in 28 healthy controls with single-photon emission tomography using iodine-123 labelled 2-carbomethoxy-3-(4-iodophenyl)tropane ([¹²³I]-CIT) as the tracer. The [¹²³I]-CIT distribution showed the most prominent 5-HT activity in the medial frontal cortex, hypothalamus, midbrain and occipital cortex and the greatest DA activity in the basal ganglia. The specific binding of the 5-HT transporters in the medial frontal cortex was 0.377±0.031 and that of the DA transporters in the basal ganglia, 0.916±0.007. Gjedde-Patlak plots indicated two separate components: the first was assumed to represent 5-HT transporters with a slope of 1.29±0.27 h^–1 and the second, DA transporters with a slope of 0.30±0.04 h^–1. This distinct kinetic pattern and the fact that 5-HT and DA transporters are situated in different parts of the brain provides an opportunity to study in vivo patients suffering from various neuropsychiatric disorders.     

Site-specific conjugation of HIV-1 tat peptides to IgG: a potential route to construct radioimmunoconjugates for targeting intracellular and nuclear epitopes in cancer

Purpose Our objective was to study the cellular and nuclear uptake of ¹²³I-mouse IgG (¹²³I-mIgG) linked to peptides [GRKKRRQRRRPPQGYGC] harbouring the membrane-translocating and nuclear import sequences of HIV-1 tat protein.Methods Carbohydrates on mIgG were oxidized by NaIO₄, then reacted with a 40-fold excess of peptides. Displacement of binding of anti-mouse IgG (Fab specific; -mFab) to ¹²³I-mIgG by tat-mIgG or mIgG was compared. Internalization and nuclear translocation of ¹²³I-tat-mIgG in MDA-MB-468, MDA-MB-231 or MCF-7 breast cancer cells were measured. The immunoreactivity of imported tat-mIgG was evaluated by measuring binding of ¹²³I--mFab to cell lysate and by displacement of binding of ¹²³I-mIgG to -mFab by cell lysate. Biodistribution and nuclear uptake of ¹²³I-tat-mIgG, ¹²³I-mIgG and ¹²³I-tat were compared in mice bearing s.c. MDA-MB-468 tumours.Results There was a 15-fold decrease in affinity of -mFab for tat-mIgG compared with mIgG. Internalized radioactivity imported into the nucleus for ¹²³I-tat-mIgG in MDA-MB-468, MDA-MB-231 and MCF-7 cells was 61.5±0.6%, 60.3±3.6% and 64.7±1.0%, respectively. The binding of ¹²³I--mFab to lysate from MDA-MB-468 cells importing tat-mIgG was 17-fold higher than that for cells not exposed to tat-mIgG. Imported tat-mIgG competed with tat-mIgG for displacement of binding of ¹²³I-mIgG to -mFab. Conjugation of mIgG to tat peptides did not change tissue distribution. Nuclear localization for ¹²³I-tat-mIgG in MDA-MB-468 tumours was 28.1±5.6%, and for liver, spleen and kidneys it was 41.7±2.7%, 13.8±0.8% and 36.9±3.3%, respectively.Conclusion ¹²³I-tat-mIgG radioimunoconjugates suggest a route to the design of radiopharmaceuticals exploiting intracellular and nuclear epitopes.     

Brain perfusion scintigraphy with99mTc-HMPAO or99mTc-ECD and123I-β-CIT single-photon emission tomography in dementia of the Alzheimer-type and diffuse Lewy body disease

Dementia of the Alzheimer-type (DAT) is characterized by progressive cognitive decline, variably combined with frontal lobe release signs, parkinsonian symptoms and myoclonus. The features of diffuse Lewy body disease (DLBD), the second most common cause of degenerative dementia, include progressive cognitive deterioration, often associated with levodopa-responsive parkinsonism, fluctuations of cognitive and motor functions, psychotic symptoms (visual and auditory hallucinations, depression), hypersensitivity to neuroleptics and orthostatic hypotension. A recent report suggests that positron emission tomography studies in patients with degenerative dementia may be useful in the differential diagnosis of DAT and DLBD. However, the diagnostic role of single-photon emission tomography (SPET) studies remains to be established. The aim of this study was therefore to evaluate regional cerebral perfusion [with either technetium-99m hexamethylpropylene amine oxime (^99mTc-HMPAO) or^99mTc-ethyl cysteinate dimer (^99mTc-ECD) SPET] and striatal dopamine transporter density [using iodine-123 2-carboxymethoxy-3-[4-iodophenyl]tropane (¹²³I--CIT) SPET] in patients with DAT and DLBD. Six patients with probable DAT and seven patients with probable DLBD were studied. Blinded qualitative assessment by four independent raters of^99mTc-HMPAO or^99mTc-ECD SPET studies revealed bilateral temporal and/or parietal hypoperfusion in all DAT patients. There was additional frontal hypoperfusion in two patients and occipital hypoperfusion in one patient. In the DLBD group, regional cerebral perfusion had a different pattern. In addition to temporoparietal hypoperfusion there was occipital hypoperfusion resembling a horseshoe defect in six of seven patients. In the DAT group, the mean 3-h striatal/cerebellar ratio of¹²³I--CIT binding was 2.5±0.4, with an increase to 5.5±1.1 18 h after tracer injection. In comparison, in the DLBD patients the mean 3-h striatal/cerebellar ratio of¹²³I--CIT binding was significantly reduced to 1.7±0.3, with a modest increase to 2.1±0.4 18 h after tracer injection (P<0.05, Scheffe test, ANOVA). These results suggest that^99mTc-HMPAO or^99mTc-ECD and¹²³I--CIT SPET may contribute to the differential diagnosis between DAT and DLBD, showing different perfusion patterns and more severe impairment of dopamine transporter function in DLBD than in DAT.     

Effect of adrenergic receptor ligands on metaiodobenzylguanidine uptake and storage in neuroblastoma cells

The effects of adrenergic receptor ligands on uptake and storage of the radiopharmaceutical [¹²⁵I]metaiodobenzylguanidine (MIBG) were studied in the human neuroblastoma cell line SK-N-SH. For uptake studies, cells were incubated for 15 min with varying concentrations of -agonist (clonidine, methoxamine, and xylazine), -antagonist (phentolamine, tolazoline, phenoxybenzamine, yohimbine, and prazosin), -antagonist (proranolol, atenolol), -agonist (isoprenaline and salbutamol), mixed / antagonist (labetalol), or the neuronal blocking agent guanethidine, prior to the addition of [¹²⁵I]MIBG (0.1 M). The incubation was continued for 2 h and specific cell-associated radioactivity was measured. For the storage studies, cells were incubated with [¹²⁵I]MIBG for 2 h, followed by replacement with fresh medium with or without drug (MIBG, clonidine, or yohimbine). Cell-associated radioactivity was measured at various times over the next 20 h. Propanolol reduced [¹²⁵I]MIBG uptake by approximately 30% (P<0.01) at all concentrations tested, most likely due to nonspecific membrane changes. However, incubation with the other -agonists or antagonists failed to elicit significant reductions in uptake. In contrast, all of the -agonists significantly inhibited uptake (P<0.05); guanethidine >xylazine >clonidine=methoxamine. The -antagonists demonstrated a broad range of inhibition (phenoxybenzamine phentolamine prazosin yohimbine=tolazoline)(P<0.05). The mixed ligand, labetalol, inhibited MIBG uptake in a dose-dependent manner with an apparent IC₅₀ of 0.65 M. The retention studies demonstrated that unlabeled MIBG caused profound self-inhibition (P<0.01). Clonidine produced a modest inhibition of retention and yohimbine had no effect. Labetalol, phenoxybenzamine, guanethidine, and propranolol reduced uptake of [¹²⁵I]MIBG by neuroblastoma cells in culture. Although only labetalol has been reported to cause false-negative MIBG scans, our results suggest that these other drugs have the potential to interfere with MIBG imaging and therapy, particularly at high doses. Adrenergic drugs did not alter cytoplasmic retention of [¹²⁵I]MIBG in neuroblastoma cells but may have potential in tumors such as phenochromocytoma, where granular storage of MIBG has been observed. Inhibition of [¹²⁵I]MIBG retention by unlabeled MIBG supports the use of high specific activity radioiodinated MIBG for both diagnosis and therapy.     

Stability of α-[11C]methyl-l-tryptophan brain trapping in healthy male volunteers

Purpose The purpose of this study was to assess the reproducibility in healthy volunteers of -[¹¹C]methyl-l-tryptophan ([¹¹C]MT) brain trapping imaging with positron emission tomography (PET), using volumes of interest (VOIs) and voxel-based image analysis.Methods Six right-handed healthy male volunteers (34.3±10.9 years) with a negative family history for psychiatric disorders were scanned twice in the resting condition, 22±17 days apart. An unbiased semiautomatic segmentation of the brain was used to define VOIs. The trapping constant K* (ml g^–1 min^–1) for [¹¹C]MT was calculated for the whole brain and seven brain regions using the graphical method for irreversible tracers. In addition, parametric maps of K* were obtained from dynamic scans using the same method. Comparison of test and retest K* functional images was performed using SPM99. Students paired t statistic was applied for comparisons of [¹¹C]MT brain trapping in a priori selected VOIs.Results [¹¹C]MT brain trapping in VOIs showed a mean variability 2.6±1.8% (0.3–5%) for absolute and 1.5±2.1% (1.4–4.1%) for normalized K*. Intraclass correlations between test and retest conditions were 0.61±0.34 for absolute K* values and 0.73±0.20 for K* values normalized by global mean. SPM99 analysis using a height threshold of p=0.05 (two tailed) and an extent threshold of 100 voxels showed no significant differences between scans.Conclusion Rest measurements in healthy male volunteers of the trapping constant for [¹¹C]MT, using PET, appeared to be stable during an average interval of 3 weeks.     

The stereoisomers of 17α-[123I]iodovinyloestradiol and its 11α-methoxy derivative evaluated for their oestrogen receptor binding in human MCF-7 cells and rat uterus,and their distribution in immature rats

We studied the potential of both stereoisomers of 17-[¹²³I]iodovinyloestradiol (E- andZ-[¹²³I]IVE) and of 11-methoxy-17-[¹²³I]iodovinyloestradiol (E-andZ-[¹²³I]MIVE) as suitable radioligands for the imaging of oestrogen receptor(ER)-positive human breast tumours. The 17-[¹²³I]iodovinyloestradiols were prepared stereospecifically by oxidative radio-iododestannylation of the corresponding 17-tri-n-butylstannylvi-nyloestradiol precursors. Competitive binding studies were performed in order to determine the relative binding affinity (RBA) of the unlabelled 17-iodovinyloes-tradiols for the ER in both human MCF-7 breast tumour cells and rat uterine tissue, compared with that of diethylstilboestrol (DES). Target tissue uptake, retention and uptake selectivity of their¹²³I-labelled analogues were studied in immature female rats. All four 17-iodovi-nyloestradiols showed high affinity for the ER in human MCF-7 cells, as well as rat uterus. Their RBA for the ER showed the following order of decreasing potency: RBA of DES >Z-IVE >Z-MIVE >E-MIVE E-IVE. Neither of these 17-iodovinyloestradiols showed any significant binding to the sex hormone binding globulin in human plasma. The biodistribution studies showed ER-mediated uptake in the uterus, ovaries and pituitary, that ofE- andZ-[¹²³I]MIVE being higher than that ofE- andZ-[¹²³I]IVE. High target-to-non-target tissue uptake ratios, especially at longer periods after injection (up to 24 h), were exhibited by both isomers of [¹²³I]MIVE. The uterus-to-blood uptake ratio was higher for^E-[¹²³I]MIVE. However, the uterus-to-fat uptake ratio appeared to be higher for theZ-isomer of [¹²³I]MIVE, especially at 24 h after injection. Metabolic properties and temperature effects, which play a more important role in vivo, probably cause the discrepancies seen between in vitro and in vivo binding results. On the basis of their in vitro binding properties and in vivo distribution characteristics we conclude thatE- andZ-[¹²³I]MIVE could be suitable radioligands for the diagnostic imaging of ER in human breast cancer. Therefore, further studies with these radioligands in mature normal and tumour-bearing rats are warranted.     

In vitro and in vivo characterisation of nor-β-CIT: a potential radioligand for visualisation of the serotonin transporter in the brain

Radiolabelled 2-Cabomethoxy-3-(4-iodophenyl)tropane (-CIT) has been used in clinical studies for the imaging of dopamine and serotonin transporters with single-photon emission tomography (SPET). 2-Carbomethoxy-3-(4-iodophenyl)nortropane (nor--CIT) is a des-methyl analogue of -CIT, which in vitro has tenfold higher affinity (IC₅₀=0.36 nM) to the serotonin transporter than -CIT (IC₅₀=4.2 nM). Nor--CIT may thus be a useful radioligand for imaging of the serotonin transporter. In the present study iodine-125 and carbon-11 labelled nor--CIT were prepared for in vitro autoradiographic studies on post-mortem human brain cryosections and for in vivo positron emission tomography (PET) studies in Cynomolgus monkeys. Whole hemisphere autoradiography with [¹²⁵I]nor--CIT demonstrated high binding in the striatum, the thalamus and cortical regions of the human brain. Addition of a high concentration (1 M) of citalopram inhibited binding in the thalamus and the neocortex, but not in the striatum. In PET studies with [¹¹C]nor--CIT there was rapid uptake of radioactivity in the monkey brain (6% of injected dose at 15 min) and high accumulation of radioactivity in the striatum, thalamus and neocortex. Thalamus to cerebellum and cortex to cerebellum ratios were 2.5 and 1.8 at 60 min, respectively. The ratios obtained with [¹¹C]nor--CIT were 20%–40% higher than those previously obtained with [¹¹C]-CIT. Radioactivity in the thalamus and the neocortex but not in the striatum was displaceable with citalopram (5 mg/kg). In conclusion, nor--CIT binds to the serotonin transporter in the primate brain in vitro and in vivo and has potential for PET and SPET imaging of the serotonin transporter in human brain.     

Quantification of nicotinic acetylcholine receptors in human brain using [123I]5-I-A-85380 SPET

The purpose of this study was to assess the utility of a new single-photon emission tomography ligand, [¹²³I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380), to measure regional nAChR binding in human brain. Six healthy nonsmoker subjects (two men and four women, age 33±15 years) participated in both a bolus (dose: 317±42 MBq) and a bolus plus constant infusion (dose of bolus: 98±32 MBq, B/I=6.7±2.6 h, total dose: 331±55 MBq) study. The study duration was 5–8 h and 14 h in the former and the latter, respectively. Nonlinear least-squares compartmental analysis was applied to bolus studies to calculate total (V_T) and specific (V_S) distribution volumes. A two-tissue compartment model was applied to identify V_S. V_T was also calculated in B/I studies. In bolus studies, V_T was well identified by both one- and two-tissue compartment models, with a coefficient of variation of less than 5% in most regions. The two-compartment model gave V_T values of 51, 22, 27, 32, 20, 19, 20, and 17 ml cm^–3 in thalamus, cerebellum, putamen, pons, and frontal, parietal, temporal, and occipital cortices, respectively. The two-compartment model did not identify V_S well. B/I studies provided poor accuracy of V_T measurement, possibly due to deviations from equilibrium conditions. These results demonstrate the feasibility of quantifying high-affinity type nAChRs using [¹²³I]5-I-A-85380 in humans and support the use of V_T measured by bolus studies.     

The effect of levodopa therapy on dopamine transporter SPECT imaging with 123I-FP-CIT in patients with Parkinson’s disease

Purpose The aim of this study was to evaluate, by means of ¹²³I-FP-CIT SPECT, the effect of chronic treatment with levodopa on striatal dopamine transporter (DAT) in patients with Parkinsons disease.Methods Fifteen patients under stable levodopa/carbidopa monotherapy were imaged twice: at baseline on medication and after at least 20 days of treatment wash-out. DAT levels were assessed from SPECT imaging for the entire striatum, the right and left striatum, the right and left putamen and the right and left caudate, as a ratio of regional brain activities using the formula: (striatal region of interest–occipital)/occipital.Results During levodopa wash-out, despite a worsening in patients clinical disability (H&Y mean stage 2.53±0.58 versus 1.73±0.45 on therapy, p<0.001), striatal ¹²³I-FP-CIT levels were not significantly different from those at baseline in any of the brain regions examined.Conclusion The results of this study suggest that levodopa does not affect ¹²³I-FP-CIT brain imaging and confirm that it is not necessary to withdraw this medication to measure DAT levels with SPECT.     

Characterization of IMPY as a potential imaging agent for β-amyloid plaques in double transgenic PSAPP mice

Deposition of -amyloid (A) plaques in the brain is likely linked to the pathogenesis of Alzheimers disease (AD). Developing specific A aggregate-binding ligands as in vivo imaging agents may be useful for diagnosis and monitoring the progression of AD. We have prepared a thioflavin derivative, 6-iodo-2-(4-dimethylamino-)phenyl-imidazo[1,2-a]pyridine, IMPY, which is readily radiolabeled with ¹²⁵I/¹²³I for binding or single-photon emission computerized tomography (SPECT) imaging studies. Characterization of [¹²⁵I]IMPY binding to plaque-like structures was evaluated in double transgenic PSAPP mice. [¹²⁵I]IMPY labeled A plaques in transgenic mouse brain sections, and the labeling was consistent with fluorescent staining and A-specific antibody labeling. Significant amounts of A plaques present in the cortical, hippocampal, and entorhinal regions of the transgenic mouse brain were clearly detected with [¹²⁵I]IMPY via ex vivo autoradiography. In contrast, [¹²⁵I]IMPY showed little labeling in the age-matched control mouse brain. Tissue homogenate binding further corroborated the A plaque-specific distribution in various brain regions of transgenic mouse, and correlated well with the known density of A deposition. Using a tissue dissection technique, [¹²⁵I]IMPY showed a moderate increase in the cortical region of transgenic mice as compared to the age-matched controls. In vitro blocking of [¹²⁵I]IMPY by carrier observed via autoradiography in mouse brain sections was not replicated by an in vivo blocking experiment in living TT mouse brain. The failure was most likely due to a significant carrier effect, which slows down the tracer in vivo metabolism, leading to an increased brain uptake. Taken together, these data indicate that [¹²³I]IMPY is a potentially useful SPECT imaging agent for in vivo labeling of A plaques in the living brain.     

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

This report documents the radiation dosimetry of iodine-123 labelled 2-carbomethoxy-3-(4-iodophenyl)tropane [¹²³I]-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]-CIT to 185 MBq for a single study.     

Interaction of metaiodobenzylguanidine with cardioactive drugs: an in vitro study

Metaiodobenzylguanidine (MIBG), an analogue of noradrenaline, is used to explore the functional integrity of sympathetic nerve endings in the human heart. Various drugs inhibit noradrenaline transport systems and may block the uptake of MIBG. As in vivo studies of the effect of these drugs on myocardial [¹²³I]MIBG uptake are often difficult to perform, we used an in vitro human blood platelet model for this purpose. A platelet preparation from healthy volunteers was incubated with [¹²⁵I]MIBG alone or different concentrations of drugs currently used in cardiology. Labetalol and propranolol inhibited [¹²⁵I]MIBG uptake, whereas all other drugs tested (other -blockers, calcium inhibitors, digoxin and amiodarone) had no effect even at doses exceeding 50 M. The labetalol dose inhibiting 50% of [¹²⁵I]MIBG uptake was lower than the plasma concentration of this drug in treated patients, whereas the propranolol dose was higher. This in vitro study of the effect of drugs on MIBG uptake by human blood platelets is predictive of their in vivo effect on myocardial uptake of [¹²³I]MIBG in treated patients, provided that plasma concentration is taken into account.     

Myocardial beta-adrenoceptor downregulation in idiopathic dilated cardiomyopathy measured in vivo with PET using the new radioligand (S)-[11C]CGP12388

Purpose The -adrenoceptor (-AR) plays an important role in heart failure. Recently, the new tracer (S)-[¹¹C]CGP12388 has been developed. It displays excellent properties for investigation of the cardiac -ARs in vivo with positron emission tomography (PET). Furthermore, the simple production method allows its use in a routine clinical setting. The aim of this study was to investigate whether decreased myocardial -AR density in patients with idiopathic dilated cardiomyopathy (IDC) can be estimated using (S)-[¹¹C]CGP12388 PET.Methods Myocardial -AR density was investigated in six patients with IDC and six age-matched healthy controls, using (S)-[¹¹C]CGP12388 PET.Results -AR densities of 5.4±1.3 pmol/g (mean ± SD) were observed in patients; these values were significantly lower than those observed in healthy controls (8.4±1.5 pmol/g, p<0.005).Conclusion This study indicates that PET with (S)-[¹¹C]CGP12388 is applicable for the measurement of myocardial -AR density in patients. A highly significant reduction in -AR density was found in patients with IDC compared with healthy controls.     

Dopamine transporter density of basal ganglia assessed with [<Superscript>123</Superscript>I]IPT SPET in obsessive-compulsive disorder

It has been suggested that dopamine, as well as serotonin, is associated with the pathophysiology of obsessive-compulsive disorder (OCD). Thus, many studies have been performed on brain regions associated with dopamine in patients with OCD. In the present study, we investigated the DAT density of the basal ganglia using iodine-123 labelled N-(3-iodopropen-2-yl)-2-carbomethoxy-3-(4-chlorophenyl) tropane ([¹²³I]IPT) single-photon emission tomography (SPET) and evaluated the activity of the presynaptic dopamine function in patients with OCD. Fifteen patients with OCD and 19 normal control adults were included in the study. We performed brain SPET 2 h after the intravenous administration of [¹²³I]IPT and carried out both quantitative and qualitative analyses using the obtained SPET data, which were reconstructed for the assessment of the specific/non-specific dopamine transporter (DAT) binding ratio in the basal ganglia. We then investigated the correlation between the severity scores of OCD symptoms assessed with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the specific/non-specific DAT binding ratio of the basal ganglia. Compared with normal control adults, patients with OCD showed a significantly increased specific/non-specific DAT binding ratio in the right basal ganglia and a tendency towards an increased specific/non-specific DAT binding ratio in the left basal ganglia. No significant correlation was found between the total scores on the Y-BOCS and the specific/non-specific DAT binding ratio of the basal ganglia. These findings suggest that the dopaminergic neurotransmitter system of the basal ganglia in patients with OCD could be involved in the pathophysiology of OCD.