[<Superscript>99m</Superscript>Tc]Demotensin 5 and 6 in the NTS1-R-targeted imaging of tumours: synthesis and preclinical results

Purpose The aim of this study was to evaluate the applicability of [^99mTc]Demotensin 5 and 6 in the targeted diagnostic imaging of neurotensin subtype 1 receptor (NTS1-R)-expressing tumours. Methods Labelling of Demotensin 5 and 6 with ^99mTc was conducted by brief incubation with ^99mTcO₄ ⁻, SnCl₂ and citrate anions in alkaline medium at ambient temperature. Affinities of conjugates for the NTS1-R were determined by competition binding experiments in WiDr cell membranes using [¹²⁵I-Tyr³]NT as the radioligand. Saturation binding assays were conducted for [^99mTc/^99gTc]Demotensin 6 in WiDr cell membranes. Internalisation of [^99mTc]Demotensin 5 and 6 was studied at 37°C in WiDr cells. Biodistribution of [^99mTc]Demotensin 5 and 6 was performed in female Swiss nu/nu mice bearing human WiDr xenografts. Results Unlabelled conjugates showed a high affinity for the human NTS1-R (Demotensin 5 IC₅₀=0.03±0.01 nM; Demotensin 6 IC₅₀=0.08±0.02 nM), while high affinity was also exhibited by (radio)metallated [^99mTc/^99gTc]Demotensin 6 (K _d=0.13±0.01 nM). [^99mTc]Demotensin 5 and 6 internalised rapidly and specifically in WiDr cells. After injection in WiDr tumour-bearing mice, radiopeptides, and especially the doubly stabilised [^99mTc]Demotensin 6, showed NTS1-R-mediated uptake in the intestines and in the implanted tumour (4.30±0.45%ID/g at 1 h post injection) and rapid renal excretion from non-target tissues into the urine. Conclusion [^99mTc]Demotensin 6 shows a favourable preclinical profile and further testing in patients is warranted to monitor its eventual applicability as a radiotracer in the diagnostic imaging of NTS1-R-positive tumours.     

Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate

Introduction Receptor radionuclide therapy is a promising treatment modality for patients with neuroendocrine tumors for whom alternative treatments are limited. The aim of this study was to investigate the incidence of hormonal crises after therapy with the radiolabeled somatostatin analogue [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate (¹⁷⁷Lu-octreotate). Materials and methods All ¹⁷⁷Lu-octreotate treatments between January 2000 and January 2007 were investigated. Four hundred seventy-six patients with gastroenteropancreatic neuroendocrine tumors and three patients with metastatic pheochromocytoma were included for analysis. Results Four hundred seventy-nine patients received a total of 1,693 administrations of ¹⁷⁷Lu-octreotate. Six of 479 patients (1%) developed severe symptoms because of massive release of bioactive substances after the first cycle of ¹⁷⁷Lu-octreotate. One patient had a metastatic hormone-producing small intestinal carcinoid; two patients had metastatic, hormone-producing bronchial carcinoids; two patients had vasoactive intestinal polypeptide-producing pancreatic endocrine tumors (VIPomas); and one patient had a metastatic pheochromocytoma. With adequate treatment, all patients eventually recovered. Conclusion Hormonal crises after ¹⁷⁷Lu-octreotate therapy occur in 1% of patients. Generally, ¹⁷⁷Lu-octreotate therapy is well tolerated.     

[<Superscript>99m</Superscript>Tc]Demobesin 1, a novel potent bombesin analogue for GRP receptor-targeted tumour imaging

Demobesin 1 is a potent new GRP-R-selective bombesin (BN) analogue containing an open chain tetraamine chelator for stable technetium-99m binding. Following a convenient labelling protocol, the radiopeptide, [(99m)Tc]Demobesin 1, formed in nearly quantitative yields and with high specific activities. Both unlabelled and labelled peptide demonstrated high-affinity binding in membrane preparations of the human androgen-independent prostate adenocarcinoma PC-3 cell line. The IC(50) values determined for Demobesin 1 and [Tyr(4)]BN were 0.70+/-0.08 n M and 1.5+/-0.20 n M, respectively, while the K(d) defined for [(99m)Tc/(99g)Tc]Demobesin 1 was 0.67+/-0.10 n M. [(99m)Tc]Demobesin 1 was rather stable in murine plasma, whereas it degraded rapidly in kidney and liver homogenates. After injection in healthy Swiss albino mice, [(99m)Tc]Demobesin 1 accumulated very efficiently in the target organs (pancreas, intestinal tract) via a GRP-R-mediated process, as shown by in vivo receptor blocking experiments. An equally high and GRP-R-mediated uptake was exhibited by [(99m)Tc]Demobesin 1 after injection in PC-3 tumour-bearing athymic mice. The initial high radioligand uptake of 16.2+/-3.1%ID/g in the PC-3 xenografts at 1 h p.i. remained at a similar level (15.61+/-1.19%ID/g) at 4 h p.i. Even after 24 h p.i., when the radioactivity had cleared from all other tissues, a value of 5.24+/-0.67%ID/g was still observed in the tumour. The high and prolonged localization of [(99m)Tc]Demobesin 1 at the tumour site and its rapid background clearance are very promising qualities for GRP-R-targeted tumour imaging in man.     

Long-term toxicity of [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate in rats

Purpose and methods Studies on peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues have shown promising results with regard to tumour control. The efficacy of PRRT is limited by uptake and retention in the proximal tubules of the kidney, which might lead to radiation nephropathy. We investigated the long-term renal toxicity after different doses of [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate and the effects of dose fractionation and lysine co-injection in two tumour-bearing rat models. Results Significant renal toxicity was detected beyond 100 days after start of treatment as shown by elevated serum creatinine and proteinuria. Microscopically, tubules were strongly dilated with flat epithelium, containing protein cylinders. Creatinine levels rose significantly after 555 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate, but were significantly lower after 278 MBq (single injection) or two weekly doses of 278 MBq. Renal damage scores were maximal after 555 MBq and significantly lower in the 278 and 2×278 MBq groups. Three doses of 185 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate with intervals of a day, a week or a month significantly influenced serum creatinine (469±18, 134±70 and 65±15 μmol/l, respectively; p<0.001). Renal histological damage scores were not significantly influenced by dose fractionation. Lysine co-administration with three weekly treatments of 185 MBq significantly lowered serum creatinine and proteinuria. Conclusion Injection of high doses of [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate resulted in severe renal damage in rats as indicated by proteinuria, elevated serum creatinine and histological damage. This damage was dose dependent and became overt between 100 and 200 days after treatment. Dose fractionation had significant beneficial effects on kidney function. Also, lysine co-injection successfully prevented functional damage.     

Effects of therapy with [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate on endocrine function

Purpose  

Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues is a novel therapy for patients with somatostatin receptor-positive tumours. We determined the effects of PRRT with [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate (¹⁷⁷Lu-octreotate) on glucose homeostasis and the pituitary-gonadal, pituitary-thyroid and pituitary-adrenal axes.     

<Superscript>99m</Superscript>Tc-HYNIC-spermine for imaging polyamine transport system-positive tumours: preclinical evaluation

Purpose  

F14512 exploiting the polyamine transport system (PTS) for tumour cell delivery has been described as a potent antitumour agent. The optimal use of this compound will require a probe to identify tumour cells expressing a highly active PTS that might be more sensitive to the treatment. The aim of this study was to design and characterize a scintigraphic probe to evaluate its uptake in cancer cells expressing the PTS.     

Radio-guided surgery with the use of [<Superscript>99m</Superscript>Tc-EDDA/HYNIC]octreotate in intra-operative detection of neuroendocrine tumours of the gastrointestinal tract

Purpose Radio-guided surgery (RGS) is an intra-operative localising technique which enables identification of tissue “marked” by a specific radiotracer injected before surgery. It is mainly used for sentinel node mapping and for detection of parathyroid adenomas and other tumours, including neuroendocrine tumours of the gastrointestinal tract (GEP-NET). The aim of this study was to determine whether intra-operative radio-detection with the use of [^99mTc-EDDA/HYNIC]octreotate, a new somatostatin analogue, is able to reveal an unknown primary and secondary sites, thereby improving surgical treatment and the final outcome of GEP-NET. Methods The study group included nine patients with suspected GEP-NET (four carcinoids, five pancreatic NET) localised with somatostatin receptor scintigraphy (with [^99mTc-EDDA/HYNIC]octreotate), who had negative results on other pre-operative imaging tests. At surgery, suspected tumours were measured in situ and ex vivo and precise exploration of the abdominal cavity was performed with the intra-operative scintillation detector (Navigator). Results Intra-operative gamma counting localised three carcinoids. In one patient SRS was false positive (owing to inflammatory infiltration). Compared with SRS, RGS revealed additional lymph node metastases in one case. RGS resulted in successful localisation of all pancreatic NET (the smallest lesion was 8 mm in diameter). Conclusion [^99mTc-EDDA/HYNIC]octreotate SRS followed by RGS is a promising technique to improve the rate of detection and efficacy of treatment of GEP-NET, especially in the presence of occult endocrine tumours. The imaging properties of [^99mTc-EDDA/HYNIC]octreotate and the 1-day imaging protocol offer opportunities for more widespread application of this tracer followed by RGS in oncology.     

Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate

Purpose In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, the kidneys are the major dose-limiting organs, because of tubular reabsorption and retention of radioactivity. Preventing renal uptake or toxicity will allow for higher tumour radiation doses. We tested the cytoprotective drug amifostine, which selectively protects healthy tissue during chemo- and radiotherapy, for its renoprotective capacities after PRRT with high-dose [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate. Methods Male Lewis rats were injected with 278 or 555 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate to create renal damage and were followed up for 130 days. For renoprotection, rats received either amifostine or co-injection with lysine. Kidneys, blood and urine were collected for toxicity measurements. At 130 days after PRRT, a single-photon emission computed tomography (SPECT) scan was performed to quantify tubular uptake of ^99mTc-dimercaptosuccinic acid (DMSA), a measure of tubular function. Results Treatment with 555 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate resulted in body weight loss, elevated creatinine and proteinuria. Amifostine and lysine treatment significantly prevented this rise in creatinine and the level of proteinuria, but did not improve the histological damage. In contrast, after 278 MBq [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate, creatinine values were slightly, but not significantly, elevated compared with the control rats. Proteinuria and histological damage were different from controls and were significantly improved by amifostine treatment. Quantification of ^99mTc-DMSA SPECT scintigrams at 130 days after [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate therapy correlated well with 1/creatinine (r ² = 0.772, p < 0.001). Conclusion Amifostine and lysine effectively decreased functional renal damage caused by high-dose [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well as to maximise anti-tumour efficacy.     

Effect of increased <Superscript>99m</Superscript>Tc/<Superscript>99</Superscript>Tc ratios on count rates in sentinel node procedures: a randomised study

The aim of this study was to evaluate the count rates of sentinel lymph nodes (SLNs) in patients with breast cancer in the operating theatre, using ^99mTc-Nanocoll with different ratios of technetium-99m to technetium-99. After written informed consent had been obtained, we tested different ratios of ^99mTc/⁹⁹Tc-Nanocoll in a double-blinded randomised study performed in 161 patients. Twenty-five MBq/g ^99mTc-colloid albumin was prepared in vacuum. In 87 patients (group A) a 2-h elution was used and in 74 patients (group B) a 24-h elution was used. Patients were subcategorised into subgroups 1 and 3, in which an SLN procedure for breast carcinoma was performed simultaneously with lumpectomy, and subgroups 2 and 4, in which an SLN procedure was performed 2–3 weeks after prior excision biopsy. All patients were injected along the lateral border of the areola (two injections: 50 MBq/0.3 ml intradermally and 50 MBq/2 ml intraparenchymally). Ex vivo measurement of count rates was performed with a gamma probe. Comparing groups A and B in respect of registered counts per second (cps) of excised SLNs, a significant difference was found (P<0.004). When comparisons were made between subgroups 1 and 2 (2-h elution) and between subgroups 3 and 4 (24-h elution) in respect of registered cps of excised SLNs, no significant difference was found (subgroup 1 vs 2, P=0.825; subgroup 3 vs 4, P=0.915). Use of a 2-h elution in vacuum yielded a significantly higher count rate of maximum specific activity of ^99mTc-colloid albumin in SLNs than was achieved using a 24-h elution in vacuum. SLN procedures performed 2–3 weeks after prior excision biopsy proved reliable as compared to SLN procedures performed simultaneously with lumpectomy.     

<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.     

The addition of DTPA to [<Superscript>177</Superscript>Lu-DOTA<Superscript>0</Superscript>,Tyr<Superscript>3</Superscript>]octreotate prior to administration reduces rat skeleton uptake of radioactivity

Peptide receptor-targeted radionuclide therapy is nowadays also being performed with DOTA-conjugated peptides, such as [DOTA(0),Tyr(3)]octreotate, labelled with radionuclides like (177)Lu. The incorporation of (177)Lu is typically >/=99.5%; however, since a total patient dose can be as high as 800 mCi, the amount of free (177)Lu(3+) (= non-DOTA-incorporated) can be substantial. Free (177)Lu(3+) accumulates in bone with unwanted irradiation of bone marrow as a consequence. (177)Lu-DTPA is reported to be stable in serum in vitro, and in vivo it has rapid renal excretion. Transforming free Lu(3+) to Lu-DTPA might reroute this fraction from accumulation in bone to renal clearance. We therefore investigated: (a) the biodistribution in rats of (177)LuCl(3), [(177)Lu-DOTA(0),Tyr(3)]octreotate and (177)Lu-DTPA; (b) the possibilities of complexing the free (177)Lu(3+) in [(177)Lu-DOTA(0),Tyr(3)]octreotate to (177)Lu-DTPA prior to intravenous injection; and (c) the effects of free (177)Lu(3+) in [(177)Lu-DOTA(0),Tyr(3)]octreotate, in the presence and absence of DTPA, on the biodistribution in rats. (177)LuCl(3) had high skeletal uptake (i.e. 5% ID per gram femur, with localization mainly in the epiphyseal plates) and a 24-h total body retention of 80% injected dose (ID). [(177)Lu-DOTA(0),Tyr(3)]octreotate had high and specific uptake in somatostatin receptor-positive tissues, and 24-h total body retention of 19% ID. (177)Lu-DTPA had rapid renal clearance, and 24-h total body retention of 4% ID. Free (177)Lu(3+) in [(177)Lu-DOTA(0),Tyr(3)]octreotate could be complexed to (177)Lu-DTPA. Accumulation of (177)Lu in femur, blood, liver and spleen showed a dose relation to the amount of free (177)Lu(3+), while these accumulations could be normalized by the addition of DTPA. After labelling [DOTA(0),Tyr(3)]octreotate with (177)Lu the addition of DTPA prior to intravenous administration of [(177)Lu-DOTA(0),Tyr(3)]octreotate is strongly recommended.     

Questionnaire survey of hospitals in Saitama Prefecture regarding the shortage of <Superscript>99m</Superscript>Tc-labeled radiopharmaceuticals and <Superscript>99</Superscript>Mo/<Superscript>99m</Superscript>Tc generators

Objective and methods  

A questionnaire survey was conducted at all 32 hospitals in Saitama Prefecture to investigate the current difficult situation in terms of nuclear medicine management in the face of the ^99mTc shortage due to insufficient supply, and 29 hospitals (90.6%) replied.     

Single-photon agents for tumor imaging:<Superscript>201</Superscript>TI,<Superscript>99m</Superscript>Tc-MIBI,and<Superscript>99m</Superscript>Tc-tetrofosmin

This review aims at fostering comprehension and knowledge not only for expert physicians who can skillfully handle various techniques for tumor imaging but also for young practitioners in the field of nuclear medicine. As image processing software and hardware become smaller, faster and better, SPECT will adapt and incorporate these advances. A principal advantage of SPECT over PET is the more widespread availability of the equipment and lower cost for the introduction of the system in community-based facilities. Moreover, SPECT has become less dependent on a limited number of acknowledged experts for its interpretation owing to a variety of handy computer tools for imaging analyses. The increasing use of PET in tumor imaging is not necessarily proportional to the decline of SPECT. General physicians' attention to SPECT technology would also increase more by evoking their interest in "tracer imaging."     

Kinetic characterization of a novel cationic <Superscript>99m</Superscript>Tc(I)-tricarbonyl complex, <Superscript>99m</Superscript>Tc-15C5-PNP,for myocardial perfusion imaging

Background  

Intense liver uptake of ^99mTc-sestamibi (MIBI) often interferes with visualization of myocardial perfusion in the inferior wall of the left ventricle. To develop improved myocardial perfusion agents, crown ether-containing dithiocarbamates and bisphosphines have been introduced in recent years. This study was designed to investigate the myocardial imaging properties and in vivo kinetics of a cationic ^99mTc(I)-tricarbonyl complex, ^99mTc-15C5-PNP, in comparison with MIBI.     

Simultaneous <Superscript>99m</Superscript>Tc/<Superscript>201</Superscript>Tl dual-isotope SPET with Monte Carlo-based down-scatter correction

In simultaneous technetium-99m/thallium-201 dual-isotope (DI) single-photon emission tomography (SPET), down-scatter of (99m)Tc photons contaminates the (201)Tl image, which leads to a decrease in lesion contrast and loss of quantitative accuracy. Correction for down-scatter can be achieved by first reconstructing the (99m)Tc activity distribution. Subsequently, the (99m)Tc down-scatter in the (201)Tl photopeak window is simulated and used for correction during iterative reconstruction of the (201)Tl image. In this work, the down-scatter projections are calculated using a dedicated Monte Carlo simulator which is able to efficiently model the detection of lead X-rays from the collimator. An anthropomorphic torso phantom with a cardiac insert with and without cold lesions was used for evaluation of the proposed method. Excellent agreement in lesion contrast and quantitative accuracy was found between the down-scatter corrected DI-SPET (201)Tl image and the virgin (i.e. separately acquired) (201)Tl image, in particular when the effects of lead X-rays were included. Compensation for the noise added by down-scatter to the (201)Tl image can be achieved by using a 15% lower dose of (99m)Tc, a 15% increase in scan time and a 12% increase in (201)Tl dose. In conclusion, the Monte Carlo-based down-scatter correction recovers lesion contrast and quantitative accuracy in DI-SPET (201)Tl images almost perfectly. In addition, degradations due to the added noise of down-scatter in simultaneous DI-SPET can be prevented by slight adaptations to the data acquisition protocol.     

Evaluation of <Superscript>99m</Superscript>Tc-labeled antibiotics for infection detection

One of the fields of research in nuclear medicine is the development of new radiopharmaceuticals for imaging infection and inflammation in humans. For this development, several antimicrobial peptides, antibiotics, antibiotic peptide and chemotactic peptides, etc., have been radiolabeled with different radionuclides (⁶⁷Ga, ^99mTc, ¹¹¹In, ¹⁸F, ¹³¹I, etc.) and their imaging potentials studied. Actually, it is very important to distinguish between infection and inflammation. In this respect, radiolabeled antibiotics have advantages because many of the properties of the ideal infection-specific agent through antibiotics localizes in infection site. In this review, only ^99mTc-labeled antibiotics are evaluated and discussed.     

PET imaging of somatostatin receptors: design,synthesis and preclinical evaluation of a novel <Superscript>18</Superscript>F-labelled,carbohydrated analogue of octreotide

Because of the excellent nuclear properties of fluorine-18 and the growing interest in somatostatin receptor (sst) scintigraphy with PET, a novel carbohydrated (18)F-labelled sst ligand was developed and preclinically evaluated. Synthesis of N(alpha)-(1-deoxy- D-fructosyl)- N(epsilon)-(2-[(18)F]fluoropropionyl)-Lys(0)-Tyr(3)-octreotate ([(18)F]FP-Gluc-TOCA) was completed in approximately 3 h (20%-30% yield). [(19)F]FP-Gluc-TOCA showed no affinity to hsst1 and hsst3, moderate affinity to hsst4 (IC(50): 437+/-84 n M) and hsst5 (IC(50): 123+/-8.8 n M) and very high affinity to hsst2 (IC(50): 2.8+/-0.4 n M). As a result of carbohydration, lipophilicity of [(18)F]FP-Gluc-TOCA was found to be low (lg P(OW)=-1.70+/-0.02). In mice, the tracer was rapidly cleared via renal excretion (kidneys: 8.69%+/-1.09%ID/g) and showed low uptake in liver (0.72%+/-0.14%ID/g) and intestine (1.88%+/-0.52%ID/g) and high tumour uptake (13.54%+/-1.47%ID/g) (all data at 1 h p.i.). Tumour to non-tumour ratios at 60 min p.i. reached 25, 19, 7, 1.6 and 56 for blood, liver, intestine, kidney and muscle, respectively. A similar biodistribution pattern was observed in pancreatic tumour-bearing rats. Tumour uptake in rats was reduced to 36% and 18% of control (30 and 60 min) by co-injection of 500 microg Tyr(3)-octreotide, demonstrating sst-specific uptake. In a first [(18)F]FP-Gluc-TOCA-PET study of a patient with a metastatic carcinoid in the liver the tracer showed superior pharmacokinetics, e.g. rapid urinary excretion and low uptake in liver, kidney and spleen. Multiple liver lesions (SUVs ranging from 21.4 to 38.0) and previously unknown focal uptake in the abdomen (SUV 10.0) were clearly visible. This is the first report on PET imaging using an (18)F-labelled sst binding peptide; it indicates that [(18)F]FP-Gluc-TOCA offers excellent imaging characteristics and allows sst imaging with high tumour to non-tumour contrast.     

Comparative microvascular exchange kinetics of [<Superscript>77</Superscript>Br]bromide and <Superscript>99m</Superscript>Tc-DTPA in humans

The plasma clearance curves of small hydrophilic solutes comprise three exponentials, consistent with a three-compartmental distribution model. A previous comparison between inulin and diethylene triamine penta-acetic acid (DTPA) suggested that these three compartments are in series, the first being plasma and the second and third representing compartments within the extravascular space. Moreover, whilst the total distribution volumes of these two indicators were similar, the volume of the second compartment was higher for DTPA. The purpose of the current study was to investigate whether a solute smaller than DTPA, namely bromide, fits the hypothesis that the second space volume is an inverse function of the size of the solute. Two groups of subjects were studied: group A comprised eight patients undergoing routine diagnostic arteriography and group B, eight patients referred for routine measurement of glomerular filtration rate plus two normal volunteers. (99m)Tc-DTPA and sodium [(77)Br]bromide were intravenously administered simultaneously. In group A, frequent arterial samples were obtained up to 40 min after injection, and antecubital venous samples 30 s after each arterial sample. In group B, frequent venous samples were obtained up to 280 min after injection. Volume measurements based on bromide were corrected for erythrocyte bromide accumulation. In both subject groups, the normalised venous concentration ratio of bromide to DTPA, corrected for red cell bromide uptake, was significantly less than unity in the earliest blood samples, being 0.56 (SD 0.08) at 1 min, consistent with faster diffusion of bromide from plasma to interstitial fluid. Furthermore, the extraction fraction of bromide from plasma to interstitial fluid in the forearm was about 0.6, higher than that of DTPA (about 0.5) in spite of red cell bromide accumulation which equilibrated with plasma bromide within 20 s and resulted in a red cell to plasma concentration ratio of 0.51 (0.09). Nevertheless, the net extraction fractions of the two solutes approached asymptotic values with identical time courses over 20-25 min. The total volume of distribution of bromide in group B was 22.5 (3.8) litres, which was higher than that of DTPA, 18.0 (2.8) litres ( P<0.001). It was assumed that this difference was the result of intracellular bromide accumulation. After correction for this, the combined volume of the first and second spaces was significantly higher for bromide, at 13.9 (2.9) litres, than for DTPA, 12.3 (2.0) litres ( P<0.05), but the volume of the third space, 4.1 (2.8) litres, was less compared with DTPA, for which it was 5.8 (2.2) litres ( P<0.05). The proportion of the total space occupied by the first and second spaces was also higher for bromide, 0.78 (0.14), than for DTPA, for which it was 0.69 (0.09; P<0.05). These data are consistent with a three-in series-compartmental model of solute distribution in which the volume of the second space is an inverse function of solute molecular size while the volume of the third is a positive function of solute size.     

Simultaneous acquisition of <Superscript>99m</Superscript>Tc- and <Superscript>123</Superscript>I-labeled radiotracers using a preclinical SPECT scanner with CZT detectors

Objective

Simultaneous acquisition of ^99mTc and ¹²³I was evaluated using a preclinical SPECT scanner with cadmium zinc telluride (CZT)-based detectors.

Methods

10-ml cylindrical syringes contained about 37 MBq ^99mTc-tetrofosmin (^99mTc-TF) or 37 MBq ¹²³I-15-(p-iodophenyl)-3R,S-methyl pentadecanoic acid (¹²³I-BMIPP) were used to assess the relationship between these SPECT radioactive counts and radioactivity. Two 10-ml syringes contained 100 or 300 MBq ^99mTc-TF and 100 MBq ¹²³I-BMIPP to assess the influence of ^99mTc upscatter and ¹²³I downscatter, respectively. A rat-sized cylindrical phantom also contained both 100 or 300 MBq ^99mTc-TF and 100 MBq ¹²³I-BMIPP. The two 10-ml syringes and phantom were scanned using a pinhole collimator for rats. Myocardial infarction model rats were examined using 300 MBq ^99mTc-TF and 100 MBq ¹²³I-BMIPP. Two 1-ml syringes contained 105 MBq ^99mTc-labeled hexamethylpropyleneamine oxime (^99mTc-HMPAO) and 35 MBq ¹²³I-labeled N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (¹²³I-FP-CIT). The two 1-ml syringes were scanned using a pinhole collimator for mice. Normal mice were examined using 105 MBq ^99mTc-HMPAO and 35 MBq ¹²³I-FP-CIT.

Results

The relationship between SPECT radioactive counts and radioactivity was excellent. Downscatter contamination of ¹²³I-BMIPP exhibited fewer radioactive counts for 300 MBq ^99mTc-TF without scatter correction (SC) in 125–150 keV. There was no upscatter contamination of ^99mTc-TF in 150–175 keV. In the rat-sized phantom, the radioactive count ratio decreased to 4.0 % for 300 MBq ^99mTc-TF without SC in 125–150 keV. In the rats, myocardial images and radioactive counts of ^99mTc-TF with the dual tracer were identical to those of the ^99mTc-TF single injection. Downscatter contamination of ¹²³I-FP-CIT was 4.2 % without SC in 125–150 keV. In the first injection of ^99mTc-HMPAO and second injection of ¹²³I-FP-CIT, brain images and radioactive counts of ^99mTc-HMPAO with the dual tracer in normal mice also were the similar to those of the ^99mTc-HMPAO single injection. In the first injection of ¹²³I-FP-CIT and second injection of ^99mTc-HMPAO, the brain images and radioactive counts with the dual tracer were not much different from those of the ¹²³I-FP-CIT single injection.

Conclusions

Dual-tracer imaging of ^99mTc- and ¹²³I-labeled radiotracers is feasible in a preclinical SPECT scanner with CZT detector. When higher radioactivity of ^99mTc-labeled radiotracers relative to ¹²³I-labeled radiotracers is applied, correction methods are not necessarily required for the quantification of ^99mTc- and ¹²³I-labeled radiotracers when using a preclinical SPECT scanner with CZT detector.