99mTc-EDDA/HYNIC-TOC: a new 99mTc-labelled radiopharmaceutical for imaging somatostatin receptor-positive tumours; first clinical results and intra-patient comparison with 111In-labelled octreotide derivatives

[111In-diethylene triamine penta-acetic acid-D-Phe1]-octreotide (DTPA-octreotide) scintigraphy has gained widespread acceptance as a diagnostic clinical procedure in oncology for imaging somatostatin receptor-positive tumours. However, indium-111 as a radiolabel has several drawbacks, including limited availability, suboptimal gamma energy and high radiation burden to the patient. We have recently reported on the preclinical development of 99mTc-EDDA/HYNIC-TOC, a new octreotide derivative which showed promising results both in vitro and in vivo. We now report our initial clinical experiences with this new radiopharmaceutical in ten oncological patients. The clinical diagnoses were: carcinoid syndrome (n=5), thyroid cancer (n=3), pancreatic cancer (n=1) and pituitary tumour (n=1). The biodistribution and kinetics of 99mTc-EDDA/HYNIC-TOC were compared with those of 111In-DTPA-octreotide in six cases, and with those of 111In-DOTA-TOC in five cases. With the new tracer tumours were imaged within 15 min after injection and showed the highest target/non-target ratios 4 h after injection. Tumour uptake persisted up to 20 h p.i. The rate of blood clearance was similar to that of 111In-DTPA-octreotide but faster than that of 111In-DOTA-TOC, while urinary excretion was lower compared with the 111In derivatives. Semi-quantitative region of interest analysis showed that 99mTc-EDDA/HYNIC-TOC produced higher tumour/organ (target/non-target) ratios than the 111In derivatives, especially in relation to heart and muscle. Significantly more lesions could be detected in 99mTc images. We conclude that 99mTcEDDA/HYNIC-TOC shows better imaging properties for the identification of somatostatin receptor-positive tumour sites than currently available 111In-labelled octreotide derivatives.     

Image fusion analysis of 99mTc-HYNIC-Tyr3-octreotide SPECT and diagnostic CT using an immobilisation device with external markers in patients with endocrine tumours

Purpose The aim of this study was to assess the value of multimodality imaging using a novel repositioning device with external markers for fusion of single-photon emission computed tomography (SPECT) and computed tomography (CT) images. The additional benefit derived from this methodological approach was analysed in comparison with SPECT and diagnostic CT alone in terms of detection rate, reliability and anatomical assignment of abnormal findings with SPECT.Methods Fifty-three patients (30 males, 23 females) with known or suspected endocrine tumours were studied. Clinical indications for somatostatin receptor (SSTR) scintigraphy (SPECT/CT image fusion) included staging of newly diagnosed tumours (n=14) and detection of unknown primary tumour in the presence of clinical and/or biochemical suspicion of neuroendocrine malignancy (n=20). Follow-up studies after therapy were performed in 19 patients. A mean activity of 400 MBq of ^99mTc-EDDA/HYNIC-Tyr³-octreotide was given intravenously. SPECT using a dual-detector scintillation camera and diagnostic multi-detector CT were sequentially performed. To ensure reproducible positioning, patients were fixed in an individualised vacuum mattress with modality-specific external markers for co-registration. SPECT and CT data were initially interpreted separately and the fused images were interpreted jointly in consensus by nuclear medicine and diagnostic radiology physicians.Results SPECT was true-positive (TP) in 18 patients, true-negative (TN) in 16, false-negative (FN) in ten and false-positive (FP) in nine; CT was TP in 18 patients, TN in 21, FP in ten and FN in four. With image fusion (SPECT and CT), the scan result was TP in 27 patients (50.9%), TN in 25 patients (47.2%) and FN in one patient, this FN result being caused by multiple small liver metastases; sensitivity was 95% and specificity, 100%. The difference between SPECT and SPECT/CT was statistically as significant as the difference between CT and SPECT/CT image fusion (P<0.001). Twenty-seven abnormal SPECT findings in 17 patients could not be initially assigned to organs, but were clearly delineated after image fusion. In 21 patients (40%), clinically relevant information was obtained by image fusion as compared with SPECT alone.Conclusion Co-registration of SPECT and diagnostic CT using a cost-effective immobilisation device provides excellent accuracy for tumour detection of endocrine malignancies and is superior to SPECT and CT alone. Image fusion reduces false positive results and can detect additional lesions. Anatomical information provided by CT enables precise localisation of abnormalities observed in SPECT.     

<Superscript>99m</Superscript>Tc-EDDA/HYNIC-TOC and <Superscript>18</Superscript>F-FDG in thyroid cancer patients with negative <Superscript>131</Superscript>I whole-body scans

Several studies have reported on the expression of somatostatin receptors in patients with differentiated thyroid cancer (DTC). The aim of this study was to evaluate the imaging abilities of a recently developed technetium-99m labelled somatostatin analogue, ^99mTc-EDDA/HYNIC-TOC (^99mTc-TOC), in terms of precise localisation of disease. The study population comprised 54 patients (24 men, 30 women; age range 22–90 years) with histologically confirmed DTC who presented with recurrent or persistent disease as indicated by elevated Tg levels after initial treatment. All patients were negative on the iodine-131 post-therapy whole-body scans. Fluorine-18 fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) was performed in a subgroup of 36 patients. The study population consisted of two groups: Group A (n=22) comprised patients with disease recurrence as shown by elevated Tg levels but without detectable pathology. In group B (n=32), pre-existing lesions were known. Among the 54 cases, SSTR scintigraphy was true positive in 33 (61.1%), true negative in 4 (7.4%) and false negative in 17 (31.5%) cases, which resulted in a sensitivity of 66%. A total of 138 tumour foci were localised in 33 patients. The fraction of true positive ^99mTc-TOC findings was positively correlated (P<0.01) with elevated Tg levels (higher than 30 ng/ml). Despite two false positive findings, analysis on a lesion basis demonstrated better diagnostic efficacy with ¹⁸F-FDG PET (P<0.001); however, it also revealed substantial agreement between the imaging techniques [Cohens kappa of 0.62 (0.47–0.78)]. In conclusion, scintigraphy with ^99mTc-TOC might be a promising tool for treatment planning; it is easy to perform and showed sufficient accuracy for localisation diagnostics in thyroid cancer patients with recurrent or metastatic disease.     

Full automation of 68Ga labelling of DOTA-peptides including cation exchange prepurification

Here we describe a fully automated approach for the synthesis of ⁶⁸Ga-labelled DOTA-peptides based on pre-concentration and purification of the generator eluate by using a cation exchange-cartridge and its comparison with fully automated direct labelling applying fractionated elution. Pre-concentration of the eluate on a cation exchange cartridge both using a resin-based and a disposable cation-exchange cartridge efficiently removed ⁶⁸Ge as well as major metal contaminations with Fe and Zn. This resulted in a high labelling efficiency of DOTA-peptides at high specific activity (SA) with short synthesis times.     

Myocardial fatty acid metabolism during acute cardiac allograft rejection

Fatty acids are promptly taken up, metabolised and eliminated by healthy cardiomyocytes. Cardiomyopathy, coronary heart disease and chronic rejection are known to be associated with an impaired fatty acid metabolism. It was the aim of this study to investigate fatty acid metabolism in a rat heart transplant model and to correlate scintigraphic findings with histological changes. After right-side nephrectomy of Lewis recipients Brown Norway cardiac allografts were anastomosed to the renal vessels. Animals were given no immunosuppression. The metabolism of carrier-free 17-¹²³ jodo-heptadecanoic acid (¹²³J-HDA) with a specific activity of >2×10¹⁷ Bq/ml was scintigraphically measured between days 1 and 11. An increase in the grade of rejection was observed over time. Fifty-six frames of 30 s duration each were recorded. For the region of interest (native heart, transplanted heart, left kidney) frames 10–56 were superimposed, time-activity curves generated and monoexponentially fitted. Furthermore, elimination half-life and intercepts were calculated. Following scintigraphic evaluation the animals were killed and graft as well as native hearts excised for histological examination. The uptake of the tracer identified severe grades of rejection. Elimination half-life of the tracer was twice as long from hearts with mild rejection and more than 14 times as long in severe rejection compared with no rejection. Elimination half-life and amplitude did not permit discrimination between grades 1, 2 and 3 a, but significantly decreased in groups 3 b and 4. This method therefore seems to be a valuable tool for the noninvasive detection of severe acute cardiac allograft rejection. Since fatty acid metabolism is clearly stress-dependent it remains to be seen whether this method allows detection of earlier rejection in loaded hearts.     

<Superscript>99m</Superscript>Tc-labelled HYNIC-minigastrin with reduced kidney uptake for targeting of CCK-2 receptor-positive tumours

Purpose Different attempts have been made to develop a suitable radioligand for targeting CCK-2 receptors in vivo, for staging of medullary thyroid carcinoma (MTC) and other receptor-expressing tumours. After initial successful clinical studies with [DTPA⁰,DGlu¹]minigastrin (DTPA-MG0) radiolabelled with ¹¹¹In and ⁹⁰Y, our group developed a ^99mTc-labelled radioligand, based on HYNIC-MG0. A major drawback observed with these derivatives is their high uptake by the kidneys. In this study we describe the preclinical evaluation of the optimised shortened peptide analogue, [HYNIC⁰,DGlu¹,desGlu^2–6]minigastrin (HYNIC-MG11). Methods ^99mTc labelling of HYNIC-MG11 was performed using tricine and EDDA as coligands. Stability experiments were carried out by reversed phase HPLC analysis in PBS, PBS/cysteine and plasma as well as rat liver and kidney homogenates. Receptor binding and cell uptake experiments were performed using AR4-2J rat pancreatic tumour cells. Animal biodistribution was studied in AR4-2J tumour-bearing nude mice. Results Radiolabelling was performed at high specific activities and radiochemical purity was >90%. ^99mTc-EDDA-HYNIC-MG11 showed high affinity for the CCK-2 receptor and cell internalisation comparable to that of ^99mTc-EDDA-HYNIC-MG0. Despite high stability in solution, a low metabolic stability in rat tissue homogenates was found. In a nude mouse tumour model, very low unspecific retention in most organs, rapid renal excretion with reduced renal retention and high tumour uptake were observed. Conclusion ^99mTc-EDDA-HYNIC-MG11 shows advantages over ^99mTc-EDDA-HYNIC-MG0 in terms of lower kidney retention with unchanged uptake in tumours and CCK-2 receptor-positive tissue. However, the lower metabolic stability and impurities formed in the labelling process still leave room for further improvement. Parts of this study were presented at the Annual Congress of the European Association of Nuclear Medicine, Istanbul, Turkey, October 2005 and at the 7th International Symposium on Technetium in Chemistry and Nuclear Medicine, Bressanone, Italy, September 2006.     

Unmittelbare Kreislaufwirkungen des Apomorphins

Zusammenfassung Das Apomorphin beeinflußt den Kreislauf auch unmittelbar, d. h. unabhängig vom Brechakt; es erregt den ganzen parasympathischen Zentralapparat und damit auch die Zentren für die Hemmung des Herzens und der Gefäße.Außerdem besitzt das Apomorphin noch eine peripher gefäßerweiternde Wirkung; am Froschgefäßpräparat hebt es die Wirkung von Adrenalin, nicht aber von Barium und Digitoxin auf.Mit 7 Textabbildungen.     

Comparison of different methods for radiochemical purity testing of [99mTc-EDDA-HYNIC-D-Phe1,Tyr3]-octreotide.

[99mTc-EDDA-HYNIC-D-Phe1,Tyr3]-octreotide (99mTc-EDDA-HYNIC-TOC) is an alternative radioligand for somatostatin receptor (SSTR) scintigraphy of neuroendocrine tumours. In order to allow a rapid and accurate determination of the quality in the clinical routine the aim of this study was to evaluate different methods of radiochemical purity (RCP) testing. Three different methods of RCP testing were compared: high-performance liquid chromatography (HPLC), thin layer chromatography (TLC) and minicolumn (Sep-Pak purification = SPE). HPLC was shown to be the most effective method for the quality control. The use of TLC and SPE is only recommended after sufficient practical labelling experience.