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.     

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.     

[<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.

     

Early [<Superscript>18</Superscript>F]florbetaben and [<Superscript>11</Superscript>C]PiB PET images are a surrogate biomarker of neuronal injury in Alzheimer’s disease

Purpose

[¹⁸F]FDG is a commonly used neuronal injury biomarker for early and differential diagnosis of dementia. Typically, the blood supply to the brain is closely coupled to glucose consumption. Early uptake of the Aβ tracer [¹¹C]PiB on PET images is mainly determined by cerebral blood flow and shows a high correlation with [¹⁸F]FDG uptake. Uptake data for ¹⁸F-labelled Aβ PET tracers are, however, scarce. We investigated the value of early PET images using the novel Aβ tracer [¹⁸F]FBB in the diagnosis of Alzhimers disease (AD).

Methods

This retrospective analysis included 22 patients with MCI or dementia who underwent dual time-point PET imaging with either [¹¹C]PiB (11 patients) or [¹⁸F]FBB (11 patients) in routine clinical practice. Images were acquired 1 – 9 min after administration of both tracers and 40 – 70 min and 90 – 110 min after administration of [¹¹C]PiB and [¹⁸F]FBB, respectively. The patients also underwent [¹⁸F]FDG brain PET imaging. PET data were analysed visually and semiquantitatively. Associations between early Aβ tracer uptake and dementia as well as brain atrophy were investigated.

Results

Regional visual scores of early Aβ tracer and [¹⁸F]FDG PET images were significantly correlated (Spearman’s ρ?=?0.780, P?<?0.001). Global brain visual analysis revealed identical results between early Aβ tracer and [¹⁸F]FDG PET images. In a VOI-based analysis, the early Aβ tracer data correlated significantly with the [¹⁸F]FDG data (r?=?0.779, P?<?0.001), but there were no differences between [¹⁸F]FBB and [¹¹C]PiB. Cortical SUVRs in regions typically affected in AD on early Aβ tracer and [¹⁸F]FDG PET images were correlated with MMSE scores (ρ?=?0.458, P?=?0.032, and ρ?=?0.456, P?=?0.033, respectively). A voxel-wise group-based search for areas with relatively higher tracer uptake on early Aβ tracer PET images compared with [¹⁸F]FDG PET images revealed a small cluster in the midbrain/pons; no significant clusters were found for the opposite comparison.

Conclusion

Early [¹⁸F]FBB and [¹¹C]PiB PET brain images are similar to [¹⁸F]FDG PET images in AD patients, and these tracers could potentially be used as biomarkers in place of [¹⁸F]FDG. Thus, Aβ tracer PET imaging has the potential to provide biomarker information on AD pathology and neuronal injury. The potential of this approach for supporting the diagnosis of AD needs to be confirmed in prospective studies in larger cohorts.

     

Synthesis and basic evaluation of 7α-(3-[<Superscript>18</Superscript>F]fluoropropyl)-testosterone and 7α-(3-[<Superscript>18</Superscript>F]fluoropropyl)-dihydrotestosterone

Objective

7α-Substituted androgen derivatives may have the potential to visualize androgen receptors with positron emission tomography. In the present study, we synthesized fluoropropyl derivatives of 7α-(3-[¹⁸F]fluoropropyl)-testosterone ([¹⁸F]7) and 7α-(3-[¹⁸F]fluoropropyl)-dihydrotestosterone ([¹⁸F]15), and characterized their in vitro binding, in vivo biodistribution, and performed blocking studies in mature androgen deprived male rats.

Methods

We synthesized [¹⁸F]7 and [¹⁸F]15. In vitro binding to recombinant rat AR ligand binding domain protein was determined using a competitive radiometric ligand-binding assay with the high-affinity synthetic androgen [17α-methyl-³H]-methyltrienolone ([³H]R1881). In vivo biodistribution was performed in mature male rats treated with diethylstilbestrol (chemical castration). A blocking study was performed by co-administration of dihydrotestosterone (36 µg/animal).

Results

7α-(3-Fluoropropyl)-testosterone (7) and 7α-(3-fluoropropyl)-dihydrotestosterone (15) showed competitive binding to recombinant rat AR ligand binding domain protein. The IC₅₀ value of 15 (13.0 ± 3.3 nM) was higher than 7 (47.8 ± 10.0 nM). In contrast to the AR binding affinity, the ventral prostate uptake of [¹⁸F]7 and [¹⁸F]15 at 2 h post-injection was similar (0.07 % injected dose/g of tissue). A blocking study indicated that specific binding of [¹⁸F]15 is observed in the ventral prostate. [¹⁸F]7 and [¹⁸F]15 showed moderate levels of bone uptake, which indicates moderate metabolic de-fluorination in rodents.

Conclusion

[¹⁸F]15 is better than [¹⁸F]7 in terms of radiochemical yield, in vitro binding affinity, prostate specific binding and stability against in vivo metabolic de-fluorination. However, the net uptake level of [¹⁸F]15 in prostate might be insufficient for in vivo visualization. Although [¹⁸F]7 and [¹⁸F]15 improved in vivo stability against de-fluorination, other basic characterization data in rodents were not superior to the current standard tracer 16β-[¹⁸F]fluoro-5α-dihydrotestosterone. It is also revealed that the shorter side chain length of 7α-[¹⁸F]fluoromethyl-dihydrotestosterone is superior to the longer three carbon chain in [¹⁸F]15, in terms of net prostate uptake and in vivo metabolic stability.

     

MicroPET imaging of 5-HT<Subscript>1A</Subscript> receptors in rat brain: a test–retest [<Superscript>18</Superscript>F]MPPF study

Purpose  Earlier studies have shown that positron emission tomography (PET) imaging with the radioligand [¹⁸F]MPPF allows for measuring the binding potential of serotonin 5-hydroxytryptamine_1A (5-HT_1A) receptors in different regions of animal and human brain, including that of 5-HT_1A autoreceptors in the raphe nuclei. In the present study, we sought to determine if such data could be obtained in rat, with a microPET (R4, Concorde Microsystems). Methods  Scans from isoflurane-anaesthetised rats (n = 18, including six test–retest) were co-registered with magnetic resonance imaging data, and binding potential, blood to plasma ratio and radiotracer efflux were estimated according to a simplified reference tissue model. Results  Values of binding potential for hippocampus (1.2), entorhinal cortex (1.1), septum (1.1), medial prefrontal cortex (1.0), amygdala (0.8), raphe nuclei (0.6), paraventricular hypothalamic nucleus (0.5) and raphe obscurus (0.5) were comparable to those previously measured with PET in cats, non-human primates or humans. Test–retest variability was in the order of 10% in the larger brain regions (hippocampus, medial prefrontal and entorhinal cortex) and less than 20% in small nuclei such as the septum and the paraventricular hypothalamic, basolateral amygdaloid and raphe nuclei. Conclusions  MicroPET brain imaging of 5-HT_1A receptors with [¹⁸F]MPPF thus represents a promising avenue for investigating 5-HT_1A receptor function in rat.     

[<Superscript>18</Superscript>F]FDG PET monitoring of tumour response to chemotherapy: does [<Superscript>18</Superscript>F]FDG uptake correlate with the viable tumour cell fraction?

Because metabolic changes induced by chemotherapy precede the morphological changes, fluorine-18 fluorodeoxyglucose positron emission tomography ([(18)F]FDG PET) is thought to predict response to therapy earlier and more accurately than other modalities. To be a reliable predictor of response, changes in tumour [(18)F]FDG uptake should reflect changes in viable cell fraction, but little is known about the contribution of apoptotic and necrotic cancer cells and inflammatory tissue to the [(18)F]FDG signal. In a tumour mouse model we investigated the relation between chemotherapy-induced changes in various tumoral components and tumour uptake and size. SCID mice were subcutaneously inoculated in the right thigh with 5 x 10(6) Daudi cells. When the tumour measured 15-20 mm, Endoxan was given intravenously. At different time points [1-15 days (d1-d15) after the injection of Endoxan], ex vivo autoradiography and histopathology were performed in two mice and [(18)F]FDG uptake in the tumour and tumour size were correlated with the different cell fractions measured with flow cytometry in five mice. At d1/d3, similar reductions in [(18)F]FDG uptake and viable tumoral cell fraction were observed and these reductions preceded changes in tumour size. By d8/d10, [(18)F]FDG uptake had stabilised despite a further reduction in viable tumoral cell fraction. At these time points a major inflammatory response was observed. At d15, an increase in viable tumour cells was again observed and this was accurately predicted by an increase in [(18)F]FDG uptake, while the tumour volume remained unchanged. In contrast with variations in tumour volume, [(18)F]FDG is a good marker for chemotherapy response monitoring. However, optimal timing seems crucial since a transient increase in stromal reaction may result in overestimation of the fraction of viable cells.     

Longitudinal Decline of Striatal Subregional [<Superscript>18</Superscript>F]FP-CIT Uptake in Parkinson’s Disease

Purpose

Dopamine transporter imaging is suggested to be a useful imaging biomarker for Parkinson’s disease (PD) progression and monitoring drug effects. We investigated the longitudinal decline characteristics of striatal [¹⁸F]FP-CIT uptake in PD.

Methods

We retrospectively reviewed 35 PD patients and 9 non-PD patients. All patients underwent [¹⁸F]FP-CIT PET at the initial diagnosis and follow-up. PET images were spatially normalized and analyzed with eight striatal and one occipital VOI templates. We measured the specific to non-specific binding ratio (SNBR) of the striatal subregions and calculated the absolute annual reduction (AAR) and relative annual reduction (%RAR) of the SNBRs.

Results

Total striatal SNBRs in PD patients were significantly lower than those in non-PD patients, with the most significant difference in the posterior putamen. Both AAR (0.26 ± 0.14 vs. 0.09 ± 0.19, p < 0.05) and %RAR (6.9 ± 3.5 vs. 1.2 ± 2.7, p < 0.001) of total striatal SNBRs were significantly greater in PD than non-PD patients. There were no significant differences in the AAR and %RAR of total striatal SNBRs between elderly and young onset PD. The AARs of the posterior putamen were higher in early PD than in advanced PD. Conversely, the %RARs were not significantly different between early and more advanced PD. The disease duration was significantly negatively correlated with the AAR but not with the %RAR of the posterior putamen.

Conclusions

The longitudinal decline of striatal [¹⁸F]FP-CIT uptake in PD was nonlinear and significantly faster than that in non-PD, with a different rate of decline among the striatal subregions.

     

PET imaging evaluation of [<Superscript>18</Superscript>F]DBT-10, a novel radioligand specific to α<Subscript>7</Subscript> nicotinic acetylcholine receptors,in nonhuman primates

Purpose

Positron emission tomography (PET) radioligands specific to α₇ nicotinic acetylcholine receptors (nAChRs) afford in vivo imaging of this receptor for neuropathologies such as Alzheimer’s disease, schizophrenia, and substance abuse. This work aims to characterize the kinetic properties of an α₇-nAChR-specific radioligand, 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-[¹⁸F]-fluorodibenzo[b,d]thiophene 5,5-dioxide ([¹⁸F]DBT-10), in nonhuman primates.

Methods

[¹⁸F]DBT-10 was produced via nucleophilic substitution of the nitro-precursor. Four Macaca mulatta subjects were imaged with [¹⁸F]DBT-10 PET, with measurement of [¹⁸F]DBT-10 parent concentrations and metabolism in arterial plasma. Baseline PET scans were acquired for all subjects. Following one scan, ex vivo analysis of brain tissue was performed to inspect for radiolabeled metabolites in brain. Three blocking scans with 0.69 and 1.24 mg/kg of the α₇-nAChR-specific ligand ASEM were also acquired to assess dose-dependent blockade of [¹⁸F]DBT-10 binding. Kinetic analysis of PET data was performed using the metabolite-corrected input function to calculate the parent fraction corrected total distribution volume (V _T/f _P).

Results

[¹⁸F]DBT-10 was produced within 90 min at high specific activities of 428?±?436 GBq/μmol at end of synthesis. Metabolism of [¹⁸F]DBT-10 varied across subjects, stabilizing by 120 min post-injection at parent fractions of 15–55 %. Uptake of [¹⁸F]DBT-10 in brain occurred rapidly, reaching peak standardized uptake values (SUVs) of 2.9–3.7 within 30 min. The plasma-free fraction was 18.8?±?3.4 %. No evidence for radiolabeled [¹⁸F]DBT-10 metabolites was found in ex vivo brain tissue samples. Kinetic analysis of PET data was best described by the two-tissue compartment model. Estimated V _T/f _P values were 193–376 ml/cm³ across regions, with regional rank order of thalamus?>?frontal cortex?>?striatum?>?hippocampus?>?occipital cortex?>?cerebellum?>?pons. Dose-dependent blockade of [¹⁸F]DBT-10 binding by structural analog ASEM was observed throughout the brain, and occupancy plots yielded a V _ND/f _P estimate of 20?±?16 ml/cm³.

Conclusion

These results demonstrate suitable kinetic properties of [¹⁸F]DBT-10 for in vivo quantification of α₇-nAChR binding in nonhuman primates.

     

GMP production of [<Superscript>18</Superscript>F]FDOPA and issues concerning its quality analyses as in USP “Fluorodopa F 18 Injection”

Introduction  

Lately, 6-[¹⁸F]fluoro-l-DOPA (FDOPA) has found increase in its clinical demand for whole-body positron emission tomography (PET) scans, and two key issues in fulfilling this demand are the difficulties in producing FDOPA under the recently imposed PET drug good manufacturing practice (GMP) regulations and in providing it in the quality meeting the terms of major compendia. This paper describes the approaches for the GMP production of FDOPA and for the product testing to meet the standard of United States Pharmacopeia (USP) “Fluorodopa F 18 Injection.”     

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.     

<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.     

Additional value of 16α-[<Superscript>18</Superscript>F]fluoro-17β-oestradiol PET for differential diagnosis between uterine sarcoma and leiomyoma in patients with positive or equivocal findings on [<Superscript>18</Superscript>F]fluorodeoxyglucose PET

Purpose  

Pathological data suggest that the rate of oestrogen receptor (ER) expression in uterine sarcoma is significantly lower than in leiomyoma. The present study aimed to investigate whether ER expression using ER imaging agents for positron emission tomography (PET), of which the most successful has been 16α-[¹⁸F]-fluoro-17β-oestradiol (FES), is able to add useful information to the differential diagnosis of uterine sarcoma and leiomyoma in patients with positive or equivocal findings on [¹⁸F]fluorodeoxyglucose (FDG) PET.     

Does diabetes affect [<Superscript>18</Superscript>F]FDG standardised uptake values in lung cancer?

The correlation of hyperglycaemia with decreased 2-[(18)F]fluoro-2-deoxy- D-glucose (FDG) uptake by tumours in positron emission tomography (PET) imaging has been clearly established. The available data are mainly based on non-diabetic (non-DM) patients exposed to acute hyperglycaemia after glucose infusion, and little is known about the effect of diabetes mellitus (DM) on FDG uptake by tumours. In this retrospective study we performed a comparison of the tumour uptake in 40 DM patients with the tumour uptake in 145 non-DM patients, all with primary lung malignancies. Peak standardised uptake values (SUVs) without glucose correction were calculated for the lung lesions. Mean (+/-standard deviation) blood glucose concentrations were 6.58+/-2.46 mmol/l in the DM patients and 4.39+/-0.89 mmol/l in the non-DM patients. There was no significant difference between tumour SUVs in DM patients (79 lesions), 5.86+/-3.97, and those in non-DM patients (234 lesions), 6.47+/-4.61. There was no significant difference between tumour SUVs in DM patients with blood glucose <7 mmol/l ( n=28, 64 lesions), 5.91+/-3.98, and those in DM patients with blood glucose >7 mmol/l ( n=12, 15 lesions), 5.68+/-4.09. There was also no significant difference between myocardial SUVs in the DM patients ( n=40), 3.28+/-2.75, and in a similar group of non-DM patients ( n=42), 3.30+/-2.24. We conclude that FDG uptake in lung tumours is not significantly influenced by blood glucose levels in diabetic patients whose blood glucose levels are reasonably well controlled.     

Detection of bone metastases in patients with prostate cancer by <Superscript>18</Superscript>F fluorocholine and <Superscript>18</Superscript>F fluoride PET–CT: a comparative study

Purpose  The aim of this prospective study was to compare the potential value of ¹⁸F fluorocholine (FCH) and ¹⁸F fluoride positron emission tomography (PET)–CT scanning for the detection of bony metastases from prostate cancer. Methods  Thirty-eight men (mean age, 69 ± 8 years) with biopsy-proven prostate cancer underwent both imaging modalities within a maximum interval of 2 weeks. Seventeen patients were evaluated preoperatively, and 21 patients were referred for post-operative evaluation of suspected recurrence or progression based on clinical algorithms. The number, sites and morphological patterns of bone lesions on ¹⁸F FCH and ¹⁸F fluoride PET–CT were correlated: Concordant lesions between the two modalities with corresponding changes on CT were considered to be positive for malignancy; discordant lesions were verified by follow-up examinations. The mean follow-up interval was 9.1 months. Results  Overall, 321 lesions were evaluated in this study. In a lesion-based analysis, a relatively close agreement was found between these two imaging modalities for detection of malignant bone lesions (kappa = 0.57), as well as in a patient-based analysis (kappa = 0.76). Sixteen malignant sclerotic lesions with a high density were negative in both ¹⁸F FCH and ¹⁸F fluoride PET–CT [mean Hounsfield unit (HU), 1,148 ± 364]. There was also a significant correlation between tracer intensity by SUV and density of sclerotic lesions by HU both in ¹⁸F FCH PET–CT (r = −0.28, p < 0.006) and ¹⁸F fluoride PET–CT (r = −0.20, p < 0.05). The sensitivity, specificity and accuracy of PET–CT in the detection of bone metastases in prostate cancer was 81%, 93% and 86% for ¹⁸F fluoride, and 74% (p = 0.12), 99% (p = 0.01) and 85% for FCH, respectively. ¹⁸F FCH PET–CT led to a change in the management in two out of 38 patients due to the early detection of bone marrow metastases. ¹⁸F fluoride PET–CT identified more lesions in some patients when compared with ¹⁸F FCH PET–CT but did not change patient management. Conclusion  FCH PET–CT may be superior for the early detection (i.e. bone marrow involvement) of metastatic bone disease. In patients with FCH-negative suspicious sclerotic lesions, a second bone-seeking agent (e.g. ¹⁸F fluoride) is recommended. ¹⁸F fluoride PET–CT demonstrated a higher sensitivity than ¹⁸F FCH PET–CT, but the difference was not statistically significant. Furthermore, ¹⁸F fluoride PET could be also negative in highly dense sclerotic lesions, which presumably reflects the effect of treatment. It will be important to clarify in future studies whether these lesions are clinically relevant when compared with metabolically active bone metastases.     

[<Superscript>18</Superscript>F]FBEM-Z<Subscript>HER2:342</Subscript>-Affibody molecule—a new molecular tracer for in vivo monitoring of HER2 expression by positron emission tomography

Purpose The expression of human epidermal growth factor receptor-2 (HER2) receptors in cancers is correlated with a poor prognosis. If assessed in vivo, it could be used for selection of appropriate therapy for individual patients and for monitoring of the tumor response to targeted therapies. We have radiolabeled a HER2-binding Affibody molecule with fluorine-18 for in vivo monitoring of the HER2 expression by positron emission tomography (PET). Materials and methods The HER2-binding Z_HER2:342–Cys Affibody molecule was conjugated with N-2-(4-[¹⁸F]fluorobenzamido)ethyl]maleimide ([¹⁸F]FBEM). The in vitro binding of the resulting radioconjugate was characterized by receptor saturation and competition assays. For in vivo studies, the radioconjugate was injected into the tail vein of mice bearing subcutaneous HER2-positive or HER2-negative tumors. Some of the mice were pre-treated with non-labeled Z_HER2:342−Cys. The animals were sacrificed at different times post-injection, and the radioactivity in selected tissues was measured. PET images were obtained using an animal PET scanner. Results In vitro experiments indicated specific, high-affinity binding to HER2. PET imaging revealed a high accumulation of the radioactivity in the tumor as early as 20 min after injection, with a plateau being reached after 60 min. These results were confirmed by biodistribution studies demonstrating that, as early as 1 h post-injection, the tumor to blood concentration ratio was 7.5 and increased to 27 at 4 h. Pre-saturation of the receptors with unlabeled Z_HER2:342–Cys lowered the accumulation of radioactivity in HER2-positive tumors to the levels observed in HER2-negative ones. Conclusion Our results suggest that the [¹⁸F]FBEM-Z_HER2:342 radioconjugate can be used to assess HER2 expression in vivo.     

Intra-individual comparison of p-[<Superscript>123</Superscript>I]-iodo-L-phenylalanine and L-3-[<Superscript>123</Superscript>I]-iodo-α-methyl-tyrosine for SPECT imaging of gliomas

Objectives Radioactive amino-acids accumulate in gliomas even with an intact blood-brain-barrier. L-3-[¹²³I]-iodo-α-methyl-tyrosine (IMT) is well established for SPECT imaging of gliomas. Recently, we introduced p-[¹²³I]-iodo-L-phenylalanine (IPA) for the characterisation of brain lesions. This study compares both tracers in glioma patients. Methods Eleven patients with gliomas (1 WHO grade 1, 5 grade 2, 1 grade 3, 2 grade 4 gliomas, 1 unconfirmed upgrading and 1 post-therapeutic non-neoplastic lesion) underwent SPECT imaging with IPA (early and delayed acquisitions at 30 min and 3 h) and IMT (early only). Maximum tumour-to-brain ratios (TBR) were calculated using region-of-interest analysis to assess uptake of IMT and IPA. Imaging results were compared to histopathological findings. Results Early TBRs of IMT and IPA were strongly correlated (r = 0.828, p = 0.002). TBRs were higher for IMT than IPA (1.95±0.50 versus 1.79±0.42; p < 0.05), but independent from tumour cell density (p > 0.1). Visual interpretation by different observers was more concordant for IMT-SPECT than IPA-SPECT (kappa 1.0 versus 0.774). No differences in early TBRs were observed between low-grade and high-grade gliomas for IMT (1.97±0.53 versus 2.21±0.44, p > 0.5) or IPA (1.70±0.23 versus 2.21±0.56, p = 0.167) with a trend to higher TBRs in low-grade tumours for IMT (p = 0.093). In contrast to the known wash-out of IMT, we observed persistent accumulation of IPA in gliomas. Conclusions IPA shows lower TBRs than IMT, especially in low-grade tumours, so IMT should be preferred for the delineation of low-grade gliomas by SPECT imaging. Due to its prolonged retention, however, IPA remains promising for therapeutic use in gliomas after labelling with I-131. This work was supported by a grant from the “Deutsche Krebshilfe” (70-3024-He 1).     

Assessment of α7 nicotinic acetylcholine receptor availability in juvenile pig brain with [<Superscript>18</Superscript>F]NS10743

Purpose  

To conduct a quantitative PET assessment of the specific binding sites in the brain of juvenile pigs for [¹⁸F]NS10743, a novel diazabicyclononane derivative targeting α7 nicotinic acetylcholine receptors (α7 nAChRs).     

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.

     

Quantification of [<Superscript>11</Superscript>C]GB67 binding to cardiac α<Subscript>1</Subscript>-adrenoceptors with positron emission tomography: validation in pigs

INTRODUCTION: An increase in human cardiac alpha(1)-adrenoceptor (alpha(1)-AR) density is associated with various diseases such as myocardial ischemia, congestive heart failure, hypertrophic cardiomyopathy and hypertension. Positron emission tomography (PET) with an appropriate radioligand offers the possibility of imaging receptor function in the normal and diseased heart. [(11)C]GB67, an analogue of prazosin, has been shown in rats to have potential as a PET ligand with high selectivity to alpha(1)-AR. However, alpha(1)-AR density is up to ten times higher in rat heart compared to that in man. The aim of the present preclinical study was to extend the previous evaluation to a large mammal heart, where the alpha(1)-AR density is comparable to man, and to validate a method for quantification before PET studies in man. METHODS: Seven [(11)C]GB67 PET studies, with weight-adjusted target dose of either 5.29 MBq kg(-1) (pilot, test-retest and baseline-predose studies) or 8.22 MBq kg(-1) (baseline-displacement studies), were performed in four anaesthetised pigs (39.5 +/- 3.9 kg). Total myocardial volume of distribution (V (T)) was estimated under different pharmacological conditions using compartmental analysis with a radiolabelled metabolite-corrected arterial plasma input function. A maximum possible blocking dose of 0.12 mumol kg(-1) of unlabeled GB67 was given 20 min before [(11)C]GB67 administration in the predose study and 45 min after administration of [(11)C]GB67 in the displacement study. In addition, [(15)O]CO (3,000 MBq) and [(15)O]H(2)O, with weight adjusted target dose of 10.57 MBq kg(-1), were also administered for estimation of blood volume recovery (RC) of the left ventricular cavity and myocardial perfusion (MBF), respectively. RESULTS: [(11)C]GB67 V (T) values (in ml cm(-3)) were estimated to be 24.2 +/- 5.5 (range, 17.3-31.3), 10.1 (predose) and 11.6 (displacement). MBF did not differ within each pig, including between baseline and predose conditions. Predose and displacement studies showed that specific binding of [(11)C]GB67 to myocardial alpha(1)-ARs accounts for approximately 50% of V (T). CONCLUSION: The present study offers a methodology for using [(11)C]GB67 as a radioligand to quantify human myocardial alpha(1)-ARs in clinical PET studies.