<Superscript>68</Superscript>Ga-labeled cyclic RGD dimers with Gly<Subscript>3</Subscript> and PEG<Subscript>4</Subscript> linkers: promising agents for tumor integrin α<Subscript>v</Subscript>β<Subscript>3</Subscript> PET imaging

Purpose  Radiolabeled cyclic RGD (Arg-Gly-Asp) peptides have great potential for the early tumor detection and noninvasive monitoring of tumor metastasis and therapeutic response. ¹⁸F-labeled RGD analogs ([¹⁸F]-AH111585 and [¹⁸F]Galacto-RGD) have been investigated in clinical trials for positron emission tomography (PET) imaging of integrin expression in cancer patients. To develop new RGD radiotracers with higher tumor accumulation, improved in vivo kinetics, easy availability and low cost, we developed two new RGD peptides and labeled them with generator-eluted ⁶⁸Ga (t_1/2 = 68 min) for PET imaging of integrin α_vβ₃ expression in tumor xenograft models. Materials and methods  The two new cyclic RGD dimers, E[PEG₄-c(RGDfK)]₂ (P₄-RGD2, PEG₄ = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and E[Gly₃-c(RGDfK)]₂ (G₃-RGD2, G₃ = Gly-Gly-Gly) were designed, synthesized and conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) for ⁶⁸Ga labeling. The microPET imaging and biodistribution of the ⁶⁸Ga labeled RGD tracers were investigated in integrin α_vβ₃-positive tumor xenografts. Results  The new RGD dimers with the Gly₃ and PEG₄ linkers showed higher integrin α_vβ₃ binding affinity than no-linker RGD dimer (RGD2). NOTA-G₃-RGD2 and NOTA-P₄-RGD2 could be labeled with ⁶⁸Ga within 30 min with higher purity (>98%) and specific activity (8.88–11.84 MBq/nmol). Both ⁶⁸Ga-NOTA-P₄-RGD2 and ⁶⁸Ga-NOTA-G₃-RGD2 exhibited significantly higher tumor uptake and tumor-to-normal tissue ratios than ⁶⁸Ga-NOTA-RGD2. Conclusion  Because of their high affinity, high specificity and excellent pharmacokinetic properties, further investigation of the two novel RGD dimers for clinical PET imaging of integrin α_vβ₃ expression in cancer patients is warranted. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Inter-heterogeneity and intra-heterogeneity of α<Subscript>v</Subscript>β<Subscript>3</Subscript> in non-small cell lung cancer and small cell lung cancer patients as revealed by <Superscript>68</Superscript>Ga-RGD<Subscript>2</Subscript> PET imaging

Purpose

Integrin α_vβ₃ is the therapeutic target of the anti-angiogenic drug cilengitide. The objective of this study was to compare α_vβ₃ levels in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) patients, by using the positron emission tomography (PET) tracer ⁶⁸Ga-labeled dimerized-RGD (⁶⁸Ga-RGD₂).

Methods

Thirty-one patients with pathologically confirmed lung cancer were enrolled (21 were NSCLC and 10 were SCLC). PET/CT images were acquired using ⁶⁸Ga-RGD₂.¹⁸F-FDG PET/CT images were also acquired on the consecutive day as reference. The standard uptake values (SUV) and the tumor/nontarget (T/NT) values were quantitatively compared. Expression of the angiogenesis marker α_vβ₃ in NSCLC and SCLC lesions was analyzed by immunohistochemistry.

Results

The ¹⁸F-FDG SUVmax and the SUVmean were not significantly different between NSCLC and SCLC patients. The ⁶⁸Ga-RGD₂ uptake of SCLC patients was at background levels in both SUV and T/NT measurements and was significantly lower than that of NSCLC patients. The range value of ⁶⁸Ga-RGD₂ SUVmean was 4.5 in the NSCLC group and 2.2 in the SCLC group, while the variation coefficient was 36.2% and 39.3% in NSCLC and SCLC primary lesions, respectively. Heterogeneity between primary lesions and putative distant metastases was also observed in some NSCLC cases. Immunostaining showed that α_vβ₃ integrin was expressed in the cells and neovasculature of NSCLC lesions, while SCLC samples had negative expression.

Conclusions

The uptake of ⁶⁸Ga-RGD₂ in SCLC patients is significantly lower than that in NSCLC patients, indicating a lower α_vβ₃ target level for cilengitide in SCLC. Apparent intra-tumor heterogeneities of α_vβ₃ also exist in both NSCLC and SCLC. Such inter- and intra-heterogeneity of α_vβ₃ may potentially improve current applications of α_vβ₃-targeted therapy and diagnostic imaging in lung cancer.

     

Design,synthesis and validation of integrin α<Subscript>2</Subscript>β<Subscript>1</Subscript>-targeted probe for microPET imaging of prostate cancer

Purpose  

The ability of PET to aid in the diagnosis and management of recurrent and/or disseminated metastatic prostate cancer may be enhanced by the development of novel prognostic imaging probes. Accumulating experimental evidence indicates that overexpression of integrin α₂β₁ may correlate with progression in human prostate cancer. In this study, ⁶⁴Cu-labeled integrin α₂β₁-targeted PET probes were designed and evaluated for the imaging of prostate cancer.     

PET imaging of α<Subscript>v</Subscript>β<Subscript>3</Subscript> integrin expression in tumours with <Superscript>68</Superscript>Ga-labelled mono-, di- and tetrameric RGD peptides

Purpose  

Due to the restricted expression of α_vβ₃ in tumours, α_vβ₃ is considered a suitable receptor for tumour targeting. In this study the α_vβ₃-binding characteristics of ⁶⁸Ga-labelled monomeric, dimeric and tetrameric RGD peptides were determined and compared with their ¹¹¹In-labelled counterparts.     

Improved targeting of the α<Subscript>v</Subscript>β<Subscript>3</Subscript> integrin by multimerisation of RGD peptides

Purpose The integrin α_vβ₃ is expressed on sprouting endothelial cells and on various tumour cell types. Due to the restricted expression of α_vβ₃ in tumours, α_vβ₃ is considered a suitable receptor for tumour targeting. In this study the α_vβ₃ binding characteristics of an ¹¹¹In-labelled monomeric, dimeric and tetrameric RGD analogue were compared. Methods A monomeric (E-c(RGDfK)), dimeric (E-[c(RGDfK)]₂), and tetrameric (E{E[c(RGDfK)]₂}₂) RGD peptide were synthesised, conjugated with DOTA and radiolabelled with ¹¹¹In. In vitro α_vβ₃ binding characteristics were determined in a competitive binding assay. In vivo α_vβ₃ targeting characteristics of the compounds were assessed in mice with SK-RC-52 xenografts. Results The IC₅₀ values for DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)]₂, and DOTA-E{E[c(RGDfK)]₂}₂were 120 nM, 69.9 nM and 19.6 nM, respectively. At all time points, the tumour uptake of the dimer was significantly higher as compared to that of the monomer. At 8 h p.i., tumour uptake of the tetramer (7.40±1.12%ID/g) was significantly higher than that of the monomer (2.30±0.34%ID/g), p<0.001, and the dimer (5.17±1.22%ID/g), p<0.05. At 24 h p.i., the tumour uptake was significantly higher for the tetramer (6.82±1.41%ID/g) than for the dimer (4.22±0.96%ID/g), p<0.01, and the monomer (1.90±0.29%ID/g), p<0.001. Conclusion Multimerisation of c(RGDfK) resulted in enhanced affinity for α_vβ₃ as determined in vitro. Tumour uptake of a tetrameric RGD peptide was significantly higher than that of the monomeric and dimeric analogues, presumably owing to the enhanced statistical likelihood for rebinding to α_vβ₃.     

Imaging α<Subscript>v</Subscript>β<Subscript>3</Subscript> integrin expression in skeletal metastases with <Superscript>99m</Superscript>Tc-maraciclatide single-photon emission computed tomography: detection and therapy response assessment

Purpose

Osteoclast activity is an important factor in the pathogenesis of skeletal metastases and is a potential therapeutic target. This study aimed to determine if selective uptake of ^99mTc-maraciclatide, a radiopharmaceutical targeting α_vβ₃ integrin, occurs in prostate cancer (PCa) bone metastases and to observe the changes following systemic therapy.

Methods

The study group comprised 17 men with bone-predominant metastatic PCa who underwent whole-body planar and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging with ^99mTc-maraciclatide before (n?=?17) and 12 weeks after (n?=?11) starting treatment with abiraterone. Tumour to normal bone (T:N) ratios, tumour to muscle (T:M) ratios and CT Hounsfield units (HU) were measured in up to five target metastases in each subject. An oncologist blinded to study scans assessed clinical responses up to 24 weeks using conventional criteria.

Results

Before treatment, metastases showed specific ^99mTc-maraciclatide accumulation (mean planar T:N and T:M ratios 1.43 and 3.06; SPECT T:N?and T:M ratios 3.1 and 5.19, respectively). Baseline sclerotic lesions (389–740 HU) showed lower T:M ratios (4.22 vs. 7.04, p?=?0.02) than less sclerotic/lytic lesions (46–381 HU). Patients with progressive disease (PD; n?=?5) showed increased planar T:N and T:M ratios (0.29 and 12.1%, respectively) and SPECT T:N and T:M ratios (11.9 and 20.2%, respectively). Patients without progression showed decreased planar T:N and T:M ratios (0.27 and ?8.0%, p?=?1.0 and 0.044, respectively) and SPECT T:N and T:M ratios (?21.9, and ?27.2%, p?=?0.3 and 0.036, respectively). The percentage change in CT HU was inversely correlated with the percentage change in SPECT T:M ratios (r?=??0.59, p?=?0.006).

Conclusions

^99mTc-maraciclatide accumulates in PCa bone metastases in keeping with increased α_vβ₃ integrin expression. Greater activity in metastases with lower CT density suggests that uptake is related to osteoclast activity. Changes in planar and SPECT T:M ratios after 12 weeks of treatment differed between patients with and without PD and ^99mTc-maraciclatide imaging may be a potential method for assessing early response.

     

[<Superscript>18</Superscript>F]FPRGD<Subscript>2</Subscript> PET/CT imaging of integrin α<Subscript>v</Subscript>β<Subscript>3</Subscript> levels in patients with locally advanced rectal carcinoma

Purpose

Our primary objective was to determine if [¹⁸F]FPRGD₂ PET/CT performed at baseline and/or after chemoradiotherapy (CRT) could predict tumour regression grade (TRG) in locally advanced rectal cancer (LARC). Secondary objectives were to compare baseline [¹⁸F]FPRGD₂ and [¹⁸F]FDG uptake, to evaluate the correlation between posttreatment [¹⁸F]FPRGD₂ uptake and tumour microvessel density (MVD) and to determine if [¹⁸F]FPRGD₂ and FDG PET/CT could predict disease-free survival.

Methods

Baseline [¹⁸F]FPRGD₂ and FDG PET/CT were performed in 32 consecutive patients (23 men, 9 women; mean age 63?±?8 years) with LARC before starting any therapy. A posttreatment [¹⁸F]FPRGD₂ PET/CT scan was performed in 24 patients after the end of CRT (median interval 7 weeks, range 3 – 15 weeks) and before surgery (median interval 4 days, range 1 – 15 days).

Results

All LARC showed uptake of both [¹⁸F]FPRGD₂ (SUV_max 5.4?±?1.5, range 2.7 – 9) and FDG (SUV_max 16.5?±?8, range 7.1 – 36.5). There was a moderate positive correlation between [¹⁸F]FPRGD₂ and FDG SUV_max (Pearson’s r?=?0.49, p?=?0.0026). There was a moderate negative correlation between baseline [¹⁸F]FPRGD₂ SUV_max and the TRG (Spearman’s r?=??0.37, p?=?0.037), and a [¹⁸F]FPRGD₂ SUV_max of >5.6 identified all patients with a complete response (TRG 0; AUC 0.84, 95 % CI 0.68 - 1, p?=?0.029). In the 24 patients who underwent a posttreatment [¹⁸F]FPRGD₂ PET/CT scan the response index, calculated as [(SUV_max1 ? SUV_max2)/SUV_max1] × 100 %, was not associated with TRG. Post-treatment [¹⁸F]FPRGD₂ uptake was not correlated with tumour MVD. Neither [¹⁸F]FPRGD₂ nor FDG uptake predicted disease-free survival.

Conclusion

Baseline [¹⁸F]FPRGD₂ uptake was correlated with the pathological response in patients with LARC treated with CRT. However, the specificity was too low to consider its clinical routine use.

     

<Superscript>68</Superscript>Ga-labeled multimeric RGD peptides for microPET imaging of integrin α<Subscript>v</Subscript>β<Subscript>3</Subscript> expression

PURPOSE: We and others have reported that (18)F- and (64)Cu-labeled arginine-glycine-aspartate (RGD) peptides allow positron emission tomography (PET) quantification of integrin alpha(v)beta(3) expression in vivo. However, clinical translation of these radiotracers is partially hindered by the necessity of cyclotron facility to produce the PET isotopes. Generator-based PET isotope (68)Ga, with a half-life of 68 min and 89% positron emission, deserves special attention because of its independence of an onsite cyclotron. The goal of this study was to investigate the feasibility of (68)Ga-labeled RGD peptides for tumor imaging. METHODS: Three cyclic RGD peptides, c(RGDyK) (RGD1), E[c(RGDyK)](2) (RGD2), and E{E[c(RGDyK)](2)}(2) (RGD4), were conjugated with macrocyclic chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and labeled with (68)Ga. Integrin affinity and specificity of the peptide conjugates were assessed by cell-based receptor binding assay, and the tumor targeting efficacy of (68)Ga-labeled RGD peptides was evaluated in a subcutaneous U87MG glioblastoma xenograft model. RESULTS: U87MG cell-based receptor binding assay using (125)I-echistatin as radioligand showed that integrin affinity followed the order of NOTA-RGD4 > NOTA-RGD2 > NOTA-RGD1. All three NOTA conjugates allowed nearly quantitative (68)Ga-labeling within 10 min (12-17 MBq/nmol). Quantitative microPET imaging studies showed that (68)Ga-NOTA-RGD4 had the highest tumor uptake but also prominent activity accumulation in the kidneys. (68)Ga-NOTA-RGD2 had higher tumor uptake (e.g., 2.8 +/- 0.1%ID/g at 1 h postinjection) and similar pharmacokinetics (4.4 +/- 0.4 tumor/muscle ratio, 2.0 +/- 0.1 tumor/liver ratio, and 1.1 +/- 0.1 tumor/kidney ratio) compared with (68)Ga-NOTA-RGD1. CONCLUSIONS: The dimeric RGD peptide tracer (68)Ga-NOTA-RGD2 with good tumor uptake and favorable pharmacokinetics warrants further investigation for potential clinical translation to image integrin alpha(v)beta(3).     

<Superscript>18</Superscript>F-labeled mini-PEG spacered RGD dimer (<Superscript>18</Superscript>F-FPRGD2): synthesis and microPET imaging of α<Subscript>v</Subscript>β<Subscript>3</Subscript> integrin expression

Purpose We have previously reported that ¹⁸F-FB-E[c(RGDyK)]₂ (¹⁸F-FRGD2) allows quantitative PET imaging of integrin α_vβ₃ expression. However, the potential clinical translation was hampered by the relatively low radiochemical yield. The goal of this study was to improve the radiolabeling yield, without compromising the tumor targeting efficiency and in vivo kinetics, by incorporating a hydrophilic bifunctional mini-PEG spacer. Methods ¹⁸F-FB-mini-PEG-E[c(RGDyK)]₂ (¹⁸F-FPRGD2) was synthesized by coupling N-succinimidyl-4-¹⁸F-fluorobenzoate (¹⁸F-SFB) with NH₂-mini-PEG-E[c(RGDyK)]₂ (denoted as PRGD2). In vitro receptor binding affinity, metabolic stability, and integrin α_vβ₃ specificity of the new tracer ¹⁸F-FPRGD2 were assessed. The diagnostic value of ¹⁸F-FPRGD2 was evaluated in subcutaneous U87MG glioblastoma xenografted mice and in c-neu transgenic mice by quantitative microPET imaging studies. Results The decay-corrected radiochemical yield based on ¹⁸F-SFB was more than 60% with radiochemical purity of >99%. ¹⁸F-FPRGD2 had high receptor binding affinity, metabolic stability, and integrin α_vβ₃-specific tumor uptake in the U87MG glioma xenograft model comparable to those of ¹⁸F-FRGD2. The kidney uptake was appreciably lower for ¹⁸F-FPRGD2 compared with ¹⁸F-FRGD2 [2.0 ± 0.2%ID/g for ¹⁸F-FPRGD2 vs 3.0 ± 0.2%ID/g for ¹⁸F-FRGD2 at 1 h post injection (p.i.)]. The uptake in all the other organs except the urinary bladder was at background level. ¹⁸F-FPRGD2 also exhibited excellent tumor uptake in c-neu oncomice (3.6 ± 0.1%ID/g at 30 min p.i.). Conclusion Incorporation of a mini-PEG spacer significantly improved the overall radiolabeling yield of ¹⁸F-FPRGD2. ¹⁸F-FPRGD2 also had reduced renal uptake and similar tumor targeting efficacy as compared with ¹⁸F-FRGD2. Further testing and clinical translation of ¹⁸F-FPRGD2 are warranted. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Zhanhong Wu and Zi-Bo Li contributed equally to this work.     

In vivo imaging of tumour angiogenesis in mice with the α<Subscript>v</Subscript>β<Subscript>3</Subscript> integrin-targeted tracer <Superscript>99m</Superscript>Tc-RAFT-RGD

Purpose The molecular imaging of tumour neoangiogenesis currently represents a major field of research for the diagnostic and treatment strategy of solid tumours. Endothelial cells from tumour neovessels overexpress the α_vβ₃ integrin, which selectively binds to Arg-Gly-Asp (RGD)-containing peptides. We evaluated the potential of the novel radiotracer ^99mTc-RAFT-RGD for the non-invasive molecular imaging of α_vβ₃ integrin expression in mice models of tumour development. Methods ^99mTc-RAFT-RGD, ^99mTc-cRGD (specific control) and ^99mTc-RAFT-RAD (non-specific control) were injected intravenously to mice bearing B16F0 or TS/A-pc tumours. In vivo whole-body tomographic imaging and post-mortem biodistribution studies were performed 60 min following tracer injection. Adjacent tumour slices were used to compare the localisation of neovessels from immunostaining and the pattern of ^99mTc-RAFT-RGD uptake from autoradiographic ex vivo imaging. Results Biodistribution studies indicated that ^99mTc-RAFT-RGD tumour uptake was significantly higher than that of ^99mTc-RAFT-RAD in B16F0 (2.4±0.5 vs 1.0±0.1%ID/g, respectively) and in TS/A-pc tumours (2.7±0.8 vs 0.7±0.1%ID/g, respectively). Immunohistochemical and autoradiographic studies indicated that ^99mTc-RAFT-RGD intratumoural uptake preferentially occurred in angiogenic areas. Tomographic imaging allowed tumour visualisation following injection of ^99mTc-RAFT-RGD and ^99mTc-cRGD with similar tumour-to-contralateral muscle (T/CM) ratios in B16F0 and in TS/A-pc tumours whereas ^99mTc-RAFT-RAD T/CM ratios did not allow tumour imaging. In accordance with the higher level of α_vβ₃ integrin expression on TS/A-pc tumours than on B16F0 tumours as determined from western blot and immunoprecipitation analyses, the ^99mTc-RAFT-RGD T/CM ratio was significantly higher in TS/A-pc than in B16F0 tumours. Conclusion ^99mTc-RAFT-RGD allowed the in vivo imaging of α_vβ₃ integrin tumour expression.     

Reduced striatal D<Subscript>2</Subscript> receptor binding in myoclonus–dystonia

Purpose  

To study striatal dopamine D₂ receptor availability in DYT11 mutation carriers of the autosomal dominantly inherited disorder myoclonus–dystonia (M–D).     

Test–retest stability of cerebral A<Subscript>1</Subscript> adenosine receptor quantification using [<Superscript>18</Superscript>F]CPFPX and PET

PURPOSE: The goal of the present study was to evaluate the reproducibility of cerebral A1 adenosine receptor (A1AR) quantification using [18F]CPFPX and PET in a test-retest design. METHODS: Eleven healthy volunteers were studied twice. Eight brain regions ranging from high to low receptor binding were examined. [18F]CPFPX was injected as a bolus with subsequent infusion over 120 min. Various outcome parameters were compared based on either metabolite-corrected venous blood sampling [e.g. apparent equilibrium total distribution volume (DVt')] or a reference region [ratio of specific to non-specific distribution volume (BP2)]. RESULTS: Test-retest variability was low in the outcome measure BP2 (on average 5.9%) and moderate in DVt' (on average 13.2%). Regarding reproducibility, the outcome parameter BP2 showed an intra-class correlation coefficient (ICC) of 0.94 +/- 0.1. For DVt' the between-subject coefficient of variation (%CV) was similar to the within-subject %CV (around 10%), resulting in a poor ICC of 0.06 +/- 0.2. CONCLUSION: Our results suggest that quantification of [18F]CPFPX imaging is reproducible and reliable for PET studies of the cerebral A1AR. Among the outcome parameters the non-invasive measures were of superior test-retest stability over the invasive.     

In vivo imaging of integrin ανβ<Subscript>3</Subscript> expression using fluorescence-mediated tomography

Purpose Optical imaging would be desirable for cancer diagnostics since it can potentially resolve relevant oncological target structures in vivo. We therefore synthesised an αvβ₃ targeted fluorochrome and imaged tumour xenografts with different αvβ₃ expression levels using both planar and tomographic optical imaging methods. Methods An αvβ₃-targeted RGD peptide was labelled with a cyanine dye (Cy 5.5). Binding of the optical tracer was tested on M21 melanoma (n = 5), HT-1080 fibrosarcoma (n = 6) and MCF-7 adenocarcinoma (n = 5) cells and their tumour xenografts. All optical imaging studies were performed using two-dimensional planar fluorescence reflectance imaging (FRI) technology and three-dimensional fluorescence-mediated tomography (FMT). Results In vitro, the peptide-dye conjugate showed a clear binding affinity to αvβ₃-positive M21 and HT-1080 cells while αvβ₃-negative MCF-7 cells and pre-dosing with the free RGD peptide revealed little to no fluorescence. In vivo, tumour xenografts were clearly visualised by FRI and FMT up to 24 h post injection. FMT allowed quantification of the fluorochrome distribution in deeper tissue sections showing an average fluorochrome concentration of 417.61 ± 105.82 nM Cy 5.5 (M21), 353.68 ± 54.02 nM Cy 5.5 (HT-1080) and 262.83 ± 155.36 nM Cy 5.5 (MCF-7) in the target tissue 60 min after tracer administration. Competition with the free RGD peptide resulted in a reduction in the fluorochrome concentration in M21 tumour tissue (294.35 ± 84.27 nM). Conclusion RGD-Cy 5.5 combined with novel tomographic optical imaging methods allows non-invasive imaging of tumour-associated αvβ₃ expression and may thus be a promising strategy for sensitive evaluation of tumour target expression.     

Molecular imaging of σ receptors: synthesis and evaluation of the potent σ<Subscript>1</Subscript> selective radioligand [<Superscript>18</Superscript>F]fluspidine

Purpose  

Neuroimaging of σ₁ receptors in the human brain has been proposed for the investigation of the pathophysiology of neurodegenerative and psychiatric diseases. However, there is a lack of suitable ¹⁸F-labelled PET radioligands for that purpose.     

Comparison of <Superscript>99m</Superscript>Tc-labeled PR81 and its F(ab′)<Subscript>2</Subscript> fragments as radioimmunoscintigraphy agents for breast cancer imaging

Objective  

We digested anti-MUC1 monoclonal antibody PR81 to produce F(ab′)₂ fragments. A comparison was performed between the two radiolabeled PR81 and F(ab′)₂ fragments for breast tumor imaging in a mouse model.     

Decreased striatal D<Subscript>2</Subscript> receptor density associated with severe behavioral abnormality in Alzheimer’s disease

OBJECTIVES: Since patients manifesting behavioral and psychological symptoms of dementia (BPSD) are a burden for their families and caregivers, the underlying neurobiological mechanism of this condition should be clarified. Using positron emission tomography (PET), we previously reported that wandering behavior in dementia was associated with a disturbed dopaminergic neuron system. We herein investigated the relationship between the severity of BPSD and the striatal D2 receptor density in Alzheimer's disease (AD). METHODS: Ten patients with probable AD as per the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the AD and Related Disorders Association (ADRDA) criteria and five normal subjects were examined with PET. The tracer used was [11C]raclopride (D2 antagonist). The uptake of [11C] raclopride was calculated as the estimation of binding potential (BP) of the striatum to the cerebellum. The AD patients were institutionalized in multiple nursing homes, and their BPSD were evaluated by the Behavioral Pathology in AD Frequency Weighted Severity Scale (BEHAVE-AD-FW) scale (Reisberg). RESULTS: There was a significant inverse Spearman's correlation between BEHAVE-AD-FW score and the BP, especially between the score of the behavioral domain and the BP values. The BP was found to be lower in severer BPSD patients. CONCLUSIONS: Patients with AD who manifest severe BPSD may have some dysfunction of striatal dopamine metabolism compared with those without BPSD.     

Iterative reconstruction or filtered backprojection for semi-quantitative assessment of dopamine D<Subscript>2</Subscript> receptor SPECT studies?

Purpose  

In routine clinical practice striatal dopamine D₂ receptor binding is generally assessed using data reconstructed by filtered backprojection (FBP). The aim of this study was to investigate the use of an iterative reconstruction algorithm (ordered subset expectation maximization, OSEM) and to assess whether it may provide comparable or even better results than those obtained by standard FBP.     

Prediction of outcome in pediatric Hodgkin lymphoma based on interpretation of <Superscript>18</Superscript>FDG-PET/CT according to ΔSUV<Subscript>max</Subscript>, Deauville 5-point scale and IHP criteria

Objective

Minimizing side effects by using response-adopted therapy strategies plays an important role in the management of pediatric Hodgkin lymphoma (HL); however, the criteria for the definition of adequate or inadequate response are controversial. The aim of this study is to compare different methods of interpretation of ¹⁸F-FDG-PET/CT (PET) in the prediction of disease outcome in order to determine the optimum method in this regard.

Methods

Baseline, interim and post-treatment PET scans of 72 children were interpreted according to revised International Harmonization Project criteria (IHP) and Deauville criteria. Cut-off values for changes in interim and post-treatment FDG uptake (ΔSUV_max) in the prediction of progression-free survival (PFS) were measured using ROC analysis. Quantitative and visual data were compared with each other in the prediction of PFS.

Results

Mean interim and post-treatment ΔSUV_max of the primary lesions were 77.4 ± 19.5 and 68.8 ± 30.4% and respective cut-off values were 82 and 73%. However, only post-treatment ΔSUV_max yielded statistically significant results in the prediction of 3-year PFS (p = 0.043). Interim ΔSUV_max was further analyzed according to the values reported in the literature (66 and 77%) yet statistically significant results were not reached (p = 0.604 and 0.431). For interim evaluation, IHP criteria was correlated to Deauville criteria (p = 0.002 and p = 0.001) and ΔSUV_max (p = 0.03), whereas for post-treatment evaluation, significant correlation with ΔSUV_max (p = 0.04) but marginally significant (p = 0.055 and p = 0.058) correlation with Deauville criteria were achieved. Overall, 1, 3 and 5-year PFS were 95.7 ± 0.2, 89.6 ± 0.4 and 80.8 ± 0.7%, respectively. All methods demonstrated comparable performance in the prediction of 3-year PFS; however, interim PET using Deauville criteria and post-treatment PET using IHP criteria were statistically significant. All methods demonstrated high negative-predictive value but substantially low positive-predictive value.

Conclusions

Deauville criteria are superior to other methods in the prediction of pediatric HL outcome using interim PET data. On the other hand, quantitative evaluation and visual evaluation by IHP can be used reliably at the end of the treatment. In this regard, we report the optimal cut-off value of SUV_max reduction as 73%.

     

Transcellular transport of radioiodinated 3-iodo-α-methyl-L-tyrosine across monolayers of kidney epithelial cell line LLC-PK<Subscript>1</Subscript>

OBJECTIVE: 3-[123I]iodo-alpha-methyl-L-tyrosine ([123I]IMT) is an imaging agent for amino acid transport. In order to obtain fundamental data related to tumor imaging with [123I]IMT and renal physiological accumulation of [123I]IMT, we investigated the transport characteristics of [125I]IMT in porcine kidney epithelial cell line LLC-PK1 using cell monolayers grown on microporous membrane filters. METHODS: LLC-PK1 monolayers were created on a collagen-coated microporous (3 microm) membrane (4.7 cm2). To examine transcellular transport (secretion and reabsorption) and accumulation, the monolayers were incubated for up to 90 min at 37 degrees C with 18.5 kBq [125I]IMT in Dulbecco's phosphate-buffered saline (pH 7.4) as an uptake solution. After incubation, transcellular transport was assessed by quantifying the radioactivity of the solutions on each side of the monolayer. For the accumulation experiment, the cells were solubilized in NaOH solution, and the radioactivity was quantified. For the inhibition experiment, the inhibitor was added at a final concentration of 1 mM. For the pH dependence experiment, the pH of the apical-side uptake solution was varied from pH 5 to pH 8. Transport of [14C]Tyr was examined for comparison. RESULTS: Bi-directional transcellular transport of [125I]IMT was observed, corresponding to secretion and reabsorption in proximal tubule. Accumulation of [125I]IMT from the basolateral side (1.62 +/- 0.15%) and the apical side (2.62 +/- 0.35%) was observed at 90 min. 2-Amino-bicyclo[2,2,1]heptane-2-carboxylic acid (a specific inhibitor of system L), L-Tyr (mother compound of [125I]IMT) and 2-aminoisobutyric acid (an inhibitor of system L and A) inhibited both directional transport (p < 0.01) and accumulation (p < 0.01). 2-(Methylamino)isobutyric acid (a specific inhibitor of system A) appeared to inhibit transport and accumulation, but the results were not significant. Decreasing apical pH significantly enhanced accumulation of [125I]IMT from both sides (p < 0.001), whereas accumulation of mother L-Tyr was significantly suppressed. CONCLUSIONS: The inhibition experiments suggest that the main contributor to [125I]IMT transport is system L, rather than Na+ -dependent transport, in both apical and basolateral membrane. [125I]IMT was transported by the system that transported L-Tyr, but the observed pH dependence of transport suggests that different mechanisms are involved in accumulation of [125I]IMT and [14C]Tyr.     

Diagnostic value of asymmetric striatal D<Subscript>2</Subscript> receptor upregulation in Parkinson’s disease: an [<Superscript>123</Superscript>I]IBZM and [<Superscript>123</Superscript>I]FP-CIT SPECT study

Introduction Striatal postsynaptic D₂ receptors in Parkinson’s disease (PD) are thought to be upregulated in the first years of the disease, especially contralateral to the clinically most affected side. The aim of this study was to evaluate whether the highest striatal D₂ binding is found contralateral to the most affected side in PD, and whether this upregulation can be used as a diagnostic tool. Methods Cross-sectional survey was undertaken of 81 patients with clinically asymmetric PD, without antiparkinsonian drugs and with a disease duration of ≤5 years and 26 age-matched controls. Striatal D₂ binding was assessed with [¹²³I]IBZM SPECT, and severity of the presynaptic dopaminergic lesion with [¹²³I]FP-CIT SPECT. Results The mean striato-occipital ratio of [¹²³I]IBZM binding was significantly higher in PD patients (1.56 ±0.09) than in controls (1.53 ±0.06). In PD patients, higher values were found contralateral to the clinically most affected side (1.57 ±0.09 vs 1.55 ±0.10 ipsilaterally), suggesting D₂ receptor upregulation, and the reverse was seen using [¹²³I]FP-CIT SPECT. However, on an individual basis only 56% of PD patients showed this upregulation. Conclusion Our study confirms asymmetric D₂ receptor upregulation in PD. However, the sensitivity of contralateral higher striatal [¹²³I]IBZM binding is only 56%. Therefore, the presence of contralateral higher striatal IBZM binding has insufficient diagnostic accuracy for PD, and PD cannot be excluded in patients with parkinsonism and no contralateral upregulation of D₂ receptors, assessed with [¹²³I]IBZM SPECT.