Reproducibility of [<Superscript>123</Superscript>I]PE2I binding to dopamine transporters with SPECT

Purpose The iodinated cocaine derivative [¹²³I]PE2I is a new selective ligand for in vivo studies of the dopamine transporter (DAT) with SPECT. Recently, a bolus/infusion (B/I) protocol for [¹²³I]PE2I measurements of DAT density was established [Pinborg LH et al. J Nucl Med 2005;46:1119–271]. The aims of this study were, firstly, to evaluate the test–retest variability using the B/I protocol and, secondly, to evaluate the B/I approach in a new group of healthy subjects using two outcome parameters, BP₁ (C_ROI/C_plasma) and BP₂ (C_ROI/C_REF). Methods Seven healthy subjects were subjected to [¹²³I]PE2I SPECT scanning twice. For both studies, the two outcome parameters BP₁ and BP₂ were calculated based on two different methods for region of interest (ROI) delineation, namely manual delineation and probability map-based automatic delineation with MRI co-registration. Results With manual delineation, striatal test–retest variability (absolute difference between first and second scan as a percentage of the mean) of BP₁ and BP₂ was 13.9% (range 1.8–35.7%) and 4.1% (range 0.5–9.7%) respectively. The probability map-based automatic delineation resulted in striatal test–retest variability of 17.2% (range 4.3–40.5%) and 5.2% (range 0.1–10.9%) respectively. The B/I approach provided stable brain activity from 120 to 180 min post injection in both high- and low-count regions with a mean % change/hour in striatal BP₂ of 10.6. Conclusion [¹²³I]PE2I SPECT with the B/I approach yields a highly reproducible measure of striatal dopamine transporter binding. The appropriateness of a B/I protocol with a B/I ratio of 2.7 h (i.e. with a bolus worth 2.7 h of infusion) was confirmed in an independent sample of healthy subjects.     

Initial experience with SPECT examinations using [123I]IBZM as a D2-dopamine receptor antagonist in Parkinson's disease.

[123I]IBZM is a new radioactive labelled ligand which has a high affinity and specificity to D2-dopamine receptors. The in vivo kinetics of [123I]IBZM were studied in patients with unilateral and bilateral accentuated idiopathic Parkinson's disease. The uptake in the basal ganglias and the imaging properties of this D2 receptor antagonist as a radiopharmaceutical for SPECT examinations had to be investigated. 5 patients, aged 42-66 years, (2 m/3 f) were examined. Each patient received 185 MBq [123I]IBZM intravenously. Blood samples were taken 0-120 min post injection (p.i.) and time activity curves were plotted. Three SPECT examinations were performed (I: 30-50 min; II: 50-70 min; and III: 70-90 min p.i.). The count rates (counts/pixel) in the basal ganglias and the cerebellum were measured for each SPECT series on transverse slices using the region-of-interest technique. The time-activity curve of [123I]IBZM shows a rapid decline in plasma during the first 10 min followed by a plateau until 120 min after injection. The SPECT examinations demonstrate the highest count rate in the basal ganglia during SPECT series III (i.e., 70-90 min p.i.). The side-to-side difference of the count rates were in the range of 3% in four patients, and 10% in one patient. The biokinetic data of [123I]IBZM make this substance capable as a radiopharmaceutical for SPECT examinations. The basal ganglia are best visualized 70-90 min p.i., thus [123I]IBZM seems to be a promising imaging agent for diseases of the D2-dopaminergic receptor system.     

One-day protocol for imaging of the nigrostriatal dopaminergic pathway in Parkinson's disease by [123I]FPCIT SPECT.

Parkinson's disease is characterized by degeneration of dopaminergic neurons, resulting in loss of dopamine transporters in the striatum. Recently, the tracer 1231-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodoph enyl)nortropane (FPCIT) was developed for imaging dopamine transporters with SPECT. The purpose of this study was to develop an [123I]FPCIT SPECT protocol for routine clinical studies. METHODS: We examined the time course of [123I]FPCIT binding to dopamine transporters in 10 healthy volunteers and 19 patients with Parkinson's disease. RESULTS: We found that the time of peak specific striatal [123I]FPCIT binding was highly varied among subjects, but specific binding peaked in all controls and patients within 3 h postinjection. Between 3 and 6 h, the ratio of specific-to-nonspecific striatal [123I]FPCIT binding was stable in both groups, although, as expected, it was significantly lower in patients. In the patients, [123I]FPCIT binding in the putamen was lower than in the caudate nucleus, and contralateral striatal binding was significantly lower than ipsilateral striatal binding. The subgroup of patients with hemi-Parkinson's disease showed loss of striatal dopamine transporters, even on the ipsilateral side. CONCLUSION: For routine clinical [123I]FPCIT SPECT studies, we recommend imaging at a single time point, between 3 and 6 h postinjection, and using a tissue ratio as the outcome measure. The [123I]FPCIT SPECT technique is sensitive enough to distinguish control subjects from patients with Parkinson's disease, even at an early stage of the disease.     

α-Alkylation of amino acid derivatives: Synthesis and chiral resolution of [C]β-aminoisobutyric acid

A synthesis of ¹¹C-labeled β-aminoisobutyric acid ([¹¹C]β-AIB) and its enantiomeric resolution by high performance liquid chromatography (HPLC) are reported. β-Alanine ethyl ester 2 was converted to benzaldimine-β-alanine ethyl ester 3 in 87% yield. Treatment of the imine derivative 3 with lithium diisopropylamide (1.1 eq) in tetrahydrofuran at −78 °C, followed by addition of cold iodomethane (1.1 eq) produced the α-methylated benzaldimine-β-alanine ethyl ester 4 in 73% chemical yield. Deprotection of the amino group by acidic hydrolysis followed by basic hydrolysis of the ester group produced the desired product 1 in 37% chemical yield. Labeling was accomplished using [¹¹C]methyl iodide. The radiola-beled product was purified by HPLC using a semipreparative reversed-phase C-18 column and 2 mM phosphate buffer (pH 5.9) as the mobile phase. The synthesis time was 35–40 min including HPLC purification, with 20–60% radiochemical yield (decay corrected). Radiochemical purity was >99%, with average specific activity being 450 mCi/μmol. Enantiomers of β-AIB were well separated by analytical HPLC using a chiral column and aqueous perchloric acid as the mobile phase. (S)-β-AIB was eluted at 17.4 min and the (R)-enantiomer was eluted at 20.0 min when the jacketed column was maintained at low temperature by circulation of ice-cold water, and the pH of the mobile phase was 1.05.     

Differential distribution of striatal [123I]β-CIT in Parkinson’s disease and progressive supranuclear palsy, evaluated with single-photon emission tomography

Functional imaging of the presynaptic dopaminergic activity using single-photon emission tomography (SPET) and iodine-123 labelled 2-β-carboxymethoxy-3-β-(4-iodophenyl)tropane ([¹²³I]β-CIT) is important for the assessment of disease severity and progression in patients with Parkinson’s disease (PD). However, its capability to discriminate between different extrapyramidal disorders has not yet been assessed. The aim of this study was to evaluate the possibility of differentiating patients with PD and with progressive supranuclear palsy (PSP) by means of this method. The distribution of [¹²³I]β-CIT in the basal ganglia was assessed in six normal subjects, 13 petients with PD and five patients with PSP in whom the disease was mild. SPET images were obtained 24±2 h after i.v. injection of the tracer using a brain-dedicated system (CERASPECT). MR and SPET images were co-registered in four normal subjects and used to define a standard set of 16 circular regions of interest (ROIs) on the slice showing the highest striatal activity. The basal ganglia ROIs corresponded to (1) the head of caudate, (2) a region of transition between the head of caudate and the anterior putamen, (3) the anterior putamen and (4) the posterior putamen. A ratio of specific to non-displaceable striatal uptake was calculated normalising the activity of the basal ganglia ROIs to that of the occipital cortex (V3′′). ANOVA revealed a global reduction of V3′′ in all ROIs of PD and PSP patients compared with normal controls (P<0.0001). A Mann-Whitney U test showed that the difference between PD and PSP patients was statistically significant for the caudate region only (Z value: 2.6; P<0.01). By subtracting V3′′ caudate values from those of the putamen, differentiation from PSP was possible in 10/13 PD patients. In conclusion, analysis of [¹²³I]β-CIT distribution in discrete striatal areas provides information on the relative caudate-putamen damage, with different values being obtained in patients clinically diagnosed as having either PD or PSP. Received 1 February and in revised form 7 May 1998     

Molecular imaging of angiogenic therapy in peripheral vascular disease with ανβ3‐integrin‐targeted nanoparticles

Noninvasive molecular imaging of angiogenesis could play a critical role in the clinical management of peripheral vascular disease patients. The α_νβ₃‐integrin, a well‐established biomarker of neovascular proliferation, is an ideal target for molecular imaging of angiogenesis. This study investigates whether MR molecular imaging with α_νβ₃‐integrin‐targeted perfluorocarbon nanoparticles can detect the neovascular response to angiogenic therapy. Hypercholesterolemic rabbits underwent femoral artery ligation followed by no treatment or angiogenic therapy with dietary L ‐arginine. MR molecular imaging performed 10 days after vessel ligation revealed increased signal enhancement in L ‐arginine‐treated animals compared to controls. Furthermore, specifically targeted nanoparticles produced two times higher MRI signal enhancement compared to nontargeted particles, demonstrating improved identification of angiogenic vasculature with biomarker targeting. X‐ray angiography performed 40 days postligation revealed that L ‐arginine treatment increased the development of collateral vessels. Histologic staining of muscle capillaries revealed a denser pattern of microvasculature in L ‐arginine‐treated animals, confirming the MR and X‐ray imaging results. The clinical application of noninvasive molecular imaging of angiogenesis could lead to earlier and more accurate detection of therapeutic response in peripheral vascular disease patients, enabling individualized optimization for a variety of treatment strategies. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Age-related effects and gender differences in Japanese healthy controls for [<Superscript>123</Superscript>I] FP-CIT SPECT

Objective

Dopamine transporter (DAT) imaging with [¹²³I]FP-CIT (DaTSCAN) is a widely used diagnostic tool for Parkinsonism and dementia. Since it was approved by the Japanese Ministry of Health, Labor, and Welfare in 2013, there have been no articles focusing on a Japanese normal population. The aim of this study was to examine the effect of aging and gender on DAT availability in Japanese people.

Methods

SPECT imaging of 30 healthy Japanese controls (17 males, 13 females; range 50–86 years, mean 70 years) was performed. SPECT images were reconstructed using a three-dimensional order subset expectation maximization (OSEM) algorithm with correction of the point spread function and scatter correction, without attenuation correction. The specific binding ratio (SBR) was calculated by DATview software. Statistical analyses were performed using linear regression analysis, analysis of variance, and multiple comparison analysis.

Results

A strong correlation between the SBR and age was observed. The correlation coefficient in males and females were ?0.566 and ?0.502, respectively. The analysis of variance revealed that aging led to a decline of the SBR, and a significant difference (p?=?0.005) was observed among generations. Gender also affected the SBR, and there was a significant difference between males and females (p?=?0.036). The SBR in females was higher than in males. Consequently, the multiple comparison revealed a significant difference between 50s and 70s (p?=?0.015) and 50s and 80s (p?=?0.006).

Conclusions

This is the first [¹²³I]FP-CIT SPECT study on subjects with normal dopamine function in Asian countries. This study provides a database of [¹²³I]FP-CIT SPECT in Japanese healthy controls. Higher DAT availability was found in women than in men. An average age-related decline in DAT availability of 8.9% was found in both genders. The data collected in this study would be helpful for Japanese physicians to make a differential diagnosis in Parkinsonian syndrome.The registration identification number for this study is UMIN000018045.

     

Graphical analysis and simplified quantification of striatal and extrastriatal dopamine D2 receptor binding with [123I]epidepride SPECT.

The purpose of this study was to extend the graphical analysis of reversible tracer binding to account for labeled lipophilic metabolites (metabolites) in quantifying [123I]epidepride binding to striatal and extrastriatal D2 receptors and, additionally, to evaluate the feasibility of simplified analysis to measure the specific volume of distribution (V3') using single-sample blood data because the tissue ratio (RT) may be a less reliable measure of D2 binding in the presence of metabolites. METHODS: Multilinear regression analysis (MLRA) and graphical analysis (GA) using plasma parent (P) plus metabolite (M) activities as input and time activities of receptor-free (RF, cerebellum) and receptor-containing regions (RR, striatum and temporal cortex) derived V3' = (alpha(RR)(P) - alpha(RF)(P)), V3' = (1 + delta) (alpha(RR) - alpha(RF)) and RT = V3'/(V2P' + deltaV2M'), where alpha is a regression coefficient, delta is the equilibrium area ratio of M and P, and (V2P'/V2M') are the corresponding nondisplaceable distribution volumes. V3' by simplified analysis (SA) was calculated from RT determined without blood data and (V2P' + deltaV2M') with single-blood sample data. The accuracy of these three V3' values was assessed relative to the metabolite-accounted kinetic analysis (KA) for [123I]epidepride SPECT studies of 11 healthy volunteers, in which each participant had 27 scans and 30 plasma samples drawn during the 14 h after injection. RESULTS: All three V3' values (mL/g) significantly correlated with those by KA (r > or = 0.90) (striatum/temporal cortex: MLRA, 77.8 +/- 36.6/2.35 +/- 1.16; GA, 98.8 +/- 34.2/4.61 +/- 1.77; SA, 83.9 +/- 24.8/4.26 +/- 1.74; KA, 107.6 +/- 34.4/5.61 +/- 1.84). However, the correlation between RT and V3' was only moderate (r < or = 0.65) because of significant intersubject variability (23%) in (V2P' + deltaV2M'). CONCLUSION: The graphical analysis can be extended to account for metabolites in measuring D2 binding with [123I]epidepride SPECT for both high and low D2 density regions. Additionally, simplified V3' measurements with single blood sampling are feasible and may be a practical alternative to the tissue ratio RT because RT suffers as a measure of D2 binding from significant intersubject variability in the metabolite-contributed distribution volume of the nondisplaceable compartment.     

Imaging of brain tumors with L-3-[123I]iodo-alpha-methyl tyrosine and SPECT

Carbon-11-labeled amino acids have been successfully used to image brain tumors by PET. This study was undertaken to evaluate the potential of L-3-[123I]-iodo-alpha-methyl tyrosine (123IMT) for metabolic imaging of brain tumors. Ten patients (glioblastoma, oligodendroglioma, lymphoma, and metastases) had early and delayed brain SPECT with a rotating gamma camera after i.v.-injection of 200-300 MBq 123IMT. In nine patients the tumors showed intense uptake of the radiotracer. Tumor-to-brain tissue ratios were between 1.4 and 2.6. 123IMT shows potentials for monitoring the effects of brain tumor therapy.     

Relationship between clinical features of Parkinson's disease and presynaptic dopamine transporter binding assessed with [123I]IPT and single-photon emission tomography

IPT [N-(3-iodopropen-2-yl)-2-carbome-thoxy-3-(4-chlorophenyl) tropane] is a new cocain analogue which allows the presynaptic dopamine transporters to be imaged with single-photon emission tomography (SPET) as early as 1–2 h post injection. In the present study [¹²³I]IPT SPET was performed in patients with Parkinson's disease (PD) to analyse the relationship between specific dopamine tansporter binding and clinical features of the disease. Twenty-six PD patients (Hoehn and Yahr stages I-IV, age range 40–79 years) and eight age-matched controls were studied. SPET imaging was performed 90–120 min after injection of 160–185 MBq [¹²³I]IPT using a triple-head camera. For semiquantitative evaluation of specific [¹²³I]IPT binding, ratios between caudate, putamen and background regions were calculated. Specific [¹²³I]IPT uptake was significantly reduced in PD patients compared to controls. Most patients showed a marked asymmetry with a more pronounced decrease in [¹²³I]IPT binding on the side contralateral to the predominant clinical findings. The putamen was always more affected than the caudate. [¹²³I]IPT binding was significantly correlated with disease duration (r=–0.7,P<0.0001) but not with the age of PD patients (r=–0.10,P=0.61). Specific [¹²³I]IPT uptake in the caudate and putamen, and putamen to caudate ratios, decreased with increasing Hoehn and Yahr stage. Our findings indicate that [¹²³I]IPT SPET may be a useful technique to estimate the extent of nigrostriatal degeneration in PD patients. Close relationships between striatal [¹²³I]IPT binding and clinical features of the disease suggest that this method can be used to objectively follow the course and progression of PD. The reduced putamen to caudate ratios observed even in patients with mild, newly recognized symptoms indicate that particularly this parameter may help to establish the correct diagnosis in the early course of PD.     

SPECT imaging of dopamine D2 receptors with 123I-IBZM: initial experience in controls and patients with Parkinson's syndrome and Wilson's disease.

123I-(S-)-2-hydroxy-3-iodo-6-methoxy-N[(1-ethyl-2-pyrrolidinyl) methyl]-benzamide (123I-IBZM) is a highly selective CNS D2 dopamine receptor ligand suitable for SPECT. This study reports on IBZM-SPECT findings in 60 patients including eight controls and 52 patients presenting with disorders of the dopaminergic system, including idiopathic Parkinson's syndrome (IPS) (n = 18), Parkinson's syndromes of other aetiology (PS) (n = 24) and Wilson's disease (n = 10). SPECT was performed 2 h p.i. of 185 MBq 123I-IBZM. For semiquantitative evaluation basal ganglia to frontal cortex ratios (BG/FC ratios) were calculated. In controls BG/FC ratios of 1.55 +/- 0.05 S.D. were observed. Findings in IPS patients (BG/FC ratio: 1.51 +/- 0.05) were not different from controls. In PS patients striatal IBZM binding (BG/FC ratio: 1.35 +/- 0.11) was significantly (P less than 0.001) lower compared to the control and IPS groups. Asymptomatic patients with Wilson's disease presented normal IBZM binding. In those with neurologic symptoms IBZM fixation was markedly reduced. IBZM-SPECT has shown to be a suitable means for in vivo imaging of striatal dopamine D2 receptors in controls and various disorders of the dopaminergic system. Our preliminary data suggest that IBZM-SPECT is potentially useful for discriminating between IPS and PS (sensitivity: 100%; specificity: 83%). In patients with Wilson's disease IBZM accumulation seems to correlate with the presence of neurologic symptoms.     

Varenicline increases in vivo striatal dopamine D2/3 receptor binding: an ultra-high-resolution pinhole [123I]IBZM SPECT study in rats

IntroductionEx vivo storage phosphor imaging rat studies reported increased brain dopamine D_2/3 receptor (DRD_2/3) availability following treatment with varenicline, a nicotinergic drug. However, ex vivo studies can only be performed using cross-sectional designs. Small-animal imaging offers the opportunity to perform serial assessments. We evaluated whether high-resolution pinhole single photon emission computed tomography (SPECT) imaging in rats was able to reproduce previous ex vivo findings.MethodsRats were imaged for baseline striatal DRD_2/3 availability using ultra-high-resolution pinhole SPECT (U-SPECT-II) and [¹²³I]IBZM as a radiotracer, and randomized to varenicline (n=7; 2 mg/kg) or saline (n=7). Following 2 weeks of treatment, a second scan was acquired.ResultsSignificantly increased striatal DRD_2/3 availability was found following varenicline treatment compared to saline (time?treatment effect): posttreatment difference in binding potential between groups corrected for initial baseline differences was 2.039 (P=.022), indicating a large effect size (d=1.48).ConclusionsUltra-high-resolution pinhole SPECT can be used to assess varenicline-induced changes in DRD_2/3 availability in small laboratory animals over time. Future small-animal studies should include imaging techniques to enable repeated within-subjects measurements and reduce the amount of animals.     

Upregulation of putaminal dopamine D2 receptors in early Parkinson's disease: a comparative PET study with [11C] raclopride and [11C]N-methylspiperone.

Dopamine D2 receptor function was assessed in a PET study with 2 dopamine D2 receptor PET ligands, [11C]raclopride (RAC) and [11C]N-methylspiperone (NMSP), in early Parkinson's disease. METHODS: Seven patients with early Parkinson's disease and 5 healthy volunteers were studied. Each underwent PET both with reversible [11C]RAC and with irreversible [11C]NMSP. RESULTS: Upregulation of dopamine D2 receptors in the putamen contralateral to the predominant symptoms of Parkinson's disease was confirmed using both [11C]RAC and [11C]NMSP. Uptake of [11C]RAC in the contralateral putamen was 105% of uptake in the opposite putamen (P = 0.020). For [11C]NMSP, uptake in the contralateral putamen was 105% of uptake in the ipsilateral putamen (P = 0.011). No significant differences between Parkinson's disease patients and healthy volunteers were detected in any of the studied brain regions using either [11C]RAC or [11C]NMSP. No significant differences between [11C]RAC and [11C]NMSP uptake were detected in the striatum, whereas in the extrastriatal regions, [11C]NMSP showed significantly higher uptake than [11C]RAC both in healthy volunteers and in Parkinson's disease patients. CONCLUSION: This study confirms an increase in dopamine D2 receptors in the putamen contralateral to the predominant symptoms, compared with the ipsilateral putamen, in early Parkinson's disease. This increase was seen both with reversible ligand [11C]RAC and with irreversible ligand [11C]NMSP and thus does not seem a consequence of depleted endogenous dopamine.     

Evaluation of novel tropane analogues in comparison with the binding characteristics of [18F]FP-CIT and [131I]beta-CIT

This study evaluated novel potential dopamine transporter (DAT) inhibitors as ligands for positron emission tomography. Five new tropane analogs were synthesized and compared with the known ligand 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (beta-CIT) and the recently characterized ligands N-(3-iodoprop-2E-enyl)-2beta-carbomethoxy-3beta-(4-methylphenyl)-nortropane (PE2I) and 2beta-carbofluoroethoxy-3beta-(4-methylphenyl)tropane (FETT). Evaluation with autoradiography measured the ability to antagonize the binding of [(131)I]iodine-labeled beta-CIT and [(18)F]fluorine-labeled N-(3-fluoropropyl)-2beta-carbomethoxy-3beta-(4-iodo-phenyl) nortropane in rat and pig brains. The standards for comparison (PE2I and FETT) competed strongly in all regions investigated (striatum, cortex, superior colliculus and cerebellum). Of the new compounds, 2alpha-amido-fluoroethyl-3beta-(4-iodophenyl)tropane (4) and 2beta-amido-fluoroethyl-3beta-(4-iodophenyl)tropane (4a) competed strongly with [(131)I]beta-CIT in DAT-rich striatum, but also in other brain regions suggesting poor DAT selectivity. Because [(131)I]beta-CIT binds unselectively both to DAT and serotonin transporters, no definite conclusion about the selectivity of the new compounds is possible. However, preclinical studies using the compounds and labeled with fluorine-18 or iodine-131 are encouraged.     

Interactions of 16α-[F]-fluoroestradiol (FES) with sex steroid binding protein (SBP)

Fluorine-18 16alpha-Fluoroestradiol ([18F]-FES) is a positron-emitting tracer for the estrogen receptor that is used for positron emission tomography (PET) studies of tumor tissues rich in the estrogen receptor. The role of the sex steroid binding protein (SBP or SHBG) in the transport of the [18F]-FES to the estrogen-receptor-rich tissue in breast cancer patients in vivo was investigated. To determine the extent to which [18F]-FES is bound to SBP in the blood, we performed a series of studies using blood samples obtained from patients undergoing [18F]-FES PET scans. The binding of [18F]-FES to the SBP was measured using a simple protein precipitation assay. The binding of [18F]-FES metabolites to SBP was also measured. These measurements showed that the tracer was distributed between albumin and SBP, and the binding capacity of SBP was sufficient to ensure that the protein was not saturated when the tracer was fully mixed with the plasma; however, local saturation of SBP may occur when [18F]-FES is administered intravenously. Typically about 45% of [18F]-FES in circulating plasma was bound to SBP, but this fraction was dependent on the concentration of SBP in plasma. The transfer of the tracer between the two proteins was rapid, complete in less than 20 s at 0 degrees C, suggesting that the equilibrium was maintained under most circumstances and that local saturation resolved quickly when blood from the injection site entered the central circulation. These data suggest that SBP binding of [18F]-FES is significant and will affect the input function of the tracer for any model that is used for the quantitative evaluation of [18F]-FES uptake in PET studies. Estimates of equilibrium binding in blood samples are sufficient to characterize [18F]-FES binding to SBP in the circulation.