Clinical evaluation of [68Ga]Ga-DATA-TOC in comparison to [68Ga]Ga-DOTA-TOC in patients with neuroendocrine tumours.

INTRODUCTION: [68Ga]Ga-DATA-TOC is a new radiolabelled somatostatin-analogue for positron emission tomography (PET) imaging of neuroendocrine tumours. Its advantage over DOTA-conjugated compounds is the possibility for high-efficiency labelling with gallium-68 quickly at room temperature with high reliability and without the need for product purification, which enables the development of an instant kit-type labelling method. We evaluated its imaging characteristics in patients with neuroendocrine tumours in comparison to [68Ga]Ga-DOTA-TOC. METHODS: 19 patients imaged with [68Ga]Ga-DATA-TOC were retrospectively analysed and uptake in normal tissues was compared with a group of 19 patients imaged with [68Ga]Ga-DOTA-TOC. 10 patients imaged with [68Ga]Ga-DATA-TOC had a history of [68Ga]Ga-DOTA-TOC imaging before and were additionally analysed to obtain biodistribution data of both tracers in the same patients. In 5 patients showing stable disease between both examinations, tumour uptake, lesion detectability and lesion conspicuity of both tracers were evaluated. RESULTS: Uptake of [68Ga]Ga-DATA-TOC in normal organs with expression of the somatostatin receptor was 25-47% lower compared to [68Ga]Ga-DOTA-TOC. Background of [68Ga]Ga-DATA-TOC was 40-41% lower in the liver. A higher retention of [68Ga]Ga-DATA-TOC was observed in the blood (up to 67%) and in the lungs (up to 44%). Tumour uptake (SUV) was 22-31% lower for [68Ga]Ga-DATA-TOC. However, no significant differences were observed for tumour-to-background ratios and lesion detectability. Regarding liver metastases, [68Ga]Ga-DATA-TOC uptake (SUV) reached 69-73% of [68Ga]Ga-DOTA-TOC uptake, but tumour-to-background ratios of [68Ga]Ga-DATA-TOC were 105-110% of [68Ga]Ga-DOTA-TOC ratios. CONCLUSIONS, ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: We demonstrated the feasibility of the new PET tracer [68Ga]Ga-DATA-TOC for imaging of patients with neuroendocrine tumours, showing a comparable performance to [68Ga]Ga-DOTA-TOC. [68Ga]Ga-DATA-TOC has the potential for development of an instant kit-type labelling method at room temperature similar to 99mTc-labelled radiopharmaceuticals, which might help to increase the availability of 68Ga-labelled somatostatin analogues for clinical routine use.

[Somatostatin receptor PET/CT (SSTR-PET/CT)]. / Somatostatinrezeptor-PET/CT.

The present guideline is focused on quality assurance of somatostatin receptor PET/CT (SSTR-PET/CT) in oncology patients. The document has been developed by a multidisciplinary board of specialists providing consensus of definitions, prerequisites, methodology, operating procedures, assessment, and standardized reporting. In particular, imaging procedures for the two most commonly used radioligands of human SSTR, i. e. 68Ga-DOTATOC and 68Ga-DOTATATE are presented. Overall, SSTR-PET/CT requires close interdisciplinary communication and cooperation of referring and executing medical disciplines, taking into account existing guidelines and recommendations of the European and German medical societies, including the European Association of Nuclear Medicine (EANM), German Society for Endocrinology (DGE), German Society for Nuclear Medicine (DGN) and German Society for Radiology (DRG).

Changes in the expression of neurotransmitter receptors in Parkin and DJ-1 knockout mice--A quantitative multireceptor study.

Parkinson's disease (PD) is a well-characterized neurological disorder with regard to its neuropathological and symptomatic appearance. At the genetic level, mutations of particular genes, e.g. Parkin and DJ-1, were found in human hereditary PD with early onset. Neurotransmitter receptors constitute decisive elements in neural signal transduction. Furthermore, since they are often altered in neurological and psychiatric diseases, receptors have been successful targets for pharmacological agents. However, the consequences of PD-associated gene mutations on the expression of transmitter receptors are largely unknown. Therefore, we studied the expression of 16 different receptor binding sites of the neurotransmitters glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine by means of quantitative receptor autoradiography in Parkin and DJ-1 knockout mice. These knockout mice exhibit electrophysiological and behavioral deficits, but do not show the typical dopaminergic cell loss. We demonstrated differential changes of binding site densities in eleven brain regions. Most prominently, we found an up-regulation of GABA(B) and kainate receptor densities in numerous cortical areas of Parkin and DJ-1 knockout mice, as well as increased NMDA but decreased AMPA receptor densities in different brain regions of the Parkin knockout mice. The alterations of three different glutamate receptor types may indicate the potential relevance of the glutamatergic system in the pathogenesis of PD. Furthermore, the cholinergic M1, M2 and nicotinic receptors as well as the adrenergic α2 and the adenosine A(2A) receptors showed differentially increased densities in Parkin and DJ-1 knockout mice. Taken together, knockout of the PD-associated genes Parkin or DJ-1 results in differential changes of neurotransmitter receptor densities, highlighting a possible role of altered non-dopaminergic, and in particular of glutamatergic neurotransmission in PD pathogenesis.

[Peptide receptor radionuclide therapy for patients with somatostatin receptor expressing tumours. German Guideline (S1)]. / Peptidrezeptor-Radionuklidtherapie Somatostatinrezeptor-exprimierender Tumore. DGN-Leitlinie (S1).

This document describes the guideline for peptide receptor radionuclide therapy (PRRT) published by the German Society of Nuclear Medicine (DGN) and accepted by the Association of the Scientific Medical Societies in Germany (AWMF) to be included in the official AWMF Guideline Registry. These recommendations are a prerequisite for the quality management in the treatment of patients with somatostatin receptor expressing tumours using PRRT. They are aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRT and to deliver the treatment in a safe and effective manner. The recommendations are based on an interdisciplinary consensus. The document contains background information and definitions and covers the rationale, indications and contraindications for PRRT. Essential topics are the requirements for institutions performing the therapy, e. g. presence of an expert for medical physics, intense cooperation with all colleagues involved in the treatment of a patient, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how treatment has to be carried out technically. Here, quality control and documentation of labelling are of great importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with the involved medical disciplines. Generally, the decision for PRRT should be undertaken within the framework of a multi-disciplinary tumour board.

Neurotransmitter receptor density changes in Pitx3ak mice--a model relevant to Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by alterations of nigrostriatal dopaminergic neurotransmission. Compared to the wealth of data on the impairment of the dopamine system, relatively limited evidence is available concerning the role of major non-dopaminergic neurotransmitter systems in PD. Therefore, we comprehensively investigated the density and distribution of neurotransmitter receptors for glutamate, GABA, acetylcholine, adrenaline, serotonin, dopamine and adenosine in brains of homozygous aphakia mice being characterized by mutations affecting the Pitx3 gene. This genetic model exhibits crucial hallmarks of PD on the neuropathological, symptomatic and pharmacological level. Quantitative receptor autoradiography was used to characterize 19 different receptor binding sites in eleven brain regions in order to understand receptor changes on a systemic level. We demonstrated striking differential changes of neurotransmitter receptor densities for numerous receptor types and brain regions, respectively. Most prominent, a strong up-regulation of GABA receptors and associated benzodiazepine binding sites in different brain regions and concomitant down-regulations of striatal nicotinic acetylcholine and serotonergic receptor densities were found. Furthermore, the densities of glutamatergic kainate, muscarinic acetylcholine, adrenergic α1 and dopaminergic D2/D3 receptors were differentially altered. These results present novel insights into the expression of neurotransmitter receptors in Pitx3(ak) mice supporting findings on PD pathology in patients and indicating on the possible underlying mechanisms. The data suggest Pitx3(ak) mice as an appropriate new model to investigate the role of neurotransmitter receptors in PD. Our study highlights the relevance of non-dopaminergic systems in PD and for the understanding of its molecular pathology.

(68)Ge/ (68)Ga generators: past, present, and future.

In 1964, first (68)Ge/(68)Ga radionuclide generators were described. Although the generator design was by far not adequate to our today's level of chemical, radiopharmaceutical and medical expectations, it perfectly met the needs of molecular imaging of this period. (68)Ga-EDTA as directly eluted from the generators entered the field of functional diagnosis, in particular for brain imaging. A new type of generators became commercially available in the first years of the 21st century. Generator eluates based on hydrochloric acid provided "cationic" (68)Ga instead of "inert" (68)Ga-complexes and opened new pathways of Me(III) based radiopharmaceutical chemistry. The impressive success of utilizing (68)Ga- DOTA-octreotides and PET/CT instead of e.g., (111)In-DTPA-octreoscan and SPECT paved the way not only towards clinical acceptance of this particular tracer for imaging neuroendocrine tracers, but to the realisation of the great potential of the (68)Ge/(68)Ga generator for modern nuclear medicine in general. The last decade has seen a (68)Ga rush. Increasing applications of generator based (68)Ga radiopharmaceuticals (for diagnosis alone, but increasingly for treatment planning thanks to the inherent option as expressed by THERANOSTICS), now ask for further developments - towards the optimization of (68)Ge/(68)Ga generators both from chemical and regulatory points of view. Dedicated chelators may be required to broaden the feasibility of (68)Ga labeling of more sensitive targeting vectors and generator chemistry may be adopted to those chelators - or vice versa. This review describes the development and the current status of (68)Ge/(68)Ga radionuclide generators.

Post-processing via cation exchange cartridges: versatile options.

New (68)Ge/(68)Ga radionuclide generators provide the positron emitter (68)Ga (T½ = 67.7 min) as an easily available and relatively inexpensive source of a PET nuclide for labeling of interesting targeting vectors. However, currently available "ionic" (68)Ge/(68)Ga radionuclide generators are not necessarily optimized for the routine synthesis of (68)Ga-labeled radiopharmaceuticals in a clinical environment. Post-processing of (68)Ge/(68)Ga generators using cation exchange resins provides chemically and radiochemically pure (68)Ga with 97±2% within less than 4 min, with (68)Ge almost completely removed, and ready for online labeling. This simple, fast, and efficient technology can be extended for new applications. The options are (a) to transfer (68)Ga from the cation exchange resin onto an anion exchange resin, to remove acetone, and to further purify the (68)Ga, (b) to obtain (68)Ga in pure non-aqueous solution via (68)Ga(acac)(3) as a synthon for syntheses in organic solvents, and (c) to create an option toward instantaneous determination of (68)Ge breakthrough, what may be required prior to the release of (68)Ga radiopharmaceutical preparations.

(68)Ga-BPAMD: PET-imaging of bone metastases with a generator based positron emitter.

PURPOSE: Bone metastases are a serious aggravation for patients suffering from cancer. Therefore, early recognition of bone metastases is of great interest for further treatment of patients. Bisphosphonates are widely used for scintigraphy of bone lesions with (99m)Tc. Using the (68)Ge/(68)Ga generator together with a macroyclic bisphosphonate a comparable PET-tracer comes into focus. PROCEDURES: The bisphosphonate DOTA-conjugated ligand BPAMD was labelled with (68)Ga. [(68)Ga]BPAMD was evaluated in vitro concerning binding to hydroxyapatite and stability. The tracer's in vivo accumulation was determined on healthy rats and bone metastases bearing animals by µ-PET. RESULTS: BPAMD was labelled efficiently with (68)Ga after 10 min at 100°C. [(68)Ga]BPAMD showed high in vitro stability within 3h and high binding to hydroxyapatite. Consequently, µ-PET experiments revealed high accumulation of [(68)Ga]BPAMD in regions of pronounced remodelling activity like bone metastases. CONCLUSIONS: (68)Ga BPAMD reveals great potential for diagnosis of bone metastases via PET/CT. The straight forward (68)Ga-labelling could be transferred to a kit-preparation of a cyclotron-independent PET tracer instantaneously available in many clinical sites using the (68)Ge/(68)Ga generator.

Improved automated synthesis of [18F]fluoroethylcholine as a radiotracer for cancer imaging.

[(18)F]Fluoroethylcholine has been recently introduced as a promising (18)F-labelled analogue of [(11)C]choline which had been previously described as a tracer for metabolic cancer imaging with positron emission tomography (PET). Due to the practical advantages of using the longer-lived radioisotope (18)F (t(1/2)=110 min), offering the opportunity of a more widespread clinical application, we established a reliable, fully automated synthesis for its production using a modified, commercially available module. [(18)F]Fluoroethylcholine was prepared from N,N-dimethylaminoethanol by iodide catalyzed alkylation with 1-[(18)F]fluoro-2-tosylethane as alkylating agent, resulting in a total radiochemical yield of 30+/-6% after a synthesis time of 50 min. The specific activity of [(18)F]fluoroethylcholine was >55 GBq/micromol and the radiochemical purity 95-99%.

A new method for radiochemical separation of arsenic from irradiated germanium oxide.

Radioarsenic labelled radiopharmaceuticals could be a valuable asset to Positron Emission Tomography (PET). In particular, the long half-lives of (72)As (T(1/2)=26 h) and (74)As (T(1/2)=17.8 d) allow to investigate slow physiological or metabolical processes, like the enrichment and distribution of antibodies in tumor tissue. This work describes the direct production of no-carrier-added (nca) arsenic isotopes *As, with *=71, 72, 73, 74 or 77, the reaction to [*As]AsI(3) and its radiochemical separation from the irradiated solid germanium oxide via polystyrene-based solid-phase extraction. The germanium oxide target, irradiated at a cyclotron or a nuclear reactor, is dissolved in concentrated HF and Ge is separated almost quantitatively (99.97%) as [GeF(6)](2-). [*As]AsI(3) is formed by addition of potassium iodide. The radiochemical separation yield for arsenic is >90%. [*As]AsI(3) is a versatile radioarsenic labelling synthon.

Labelling of manganese-based magnetic resonance imaging (MRI) contrast agents with the positron emitter 51Mn, as exemplified by manganese-tetraphenyl-porphin-sulfonate (MnTPPS4).

The potential tumor seeking MRI contrast agent MnTPPS(4) was labelled with the positron emitting nuclide (51)Mn in no-carrier-added (n.c.a.) form. The complex formation kinetics were investigated and the apparent rate constants were determined under pseudo-first-order conditions. The derived bimolecular rate constants gave the Arrhenius parameters E(A)=84 kJ mol(-1) and A=2 x 10(12)s(-1)M(-1). Optimum labelling conditions were derived (radiochemical yields >99% possible, effective yields about 32%). Separation and purification of n.c.a. (51)MnTPPS(4) were performed for potential human use. All impurities were <1%.

An experimental comparison of the K- and L-Auger electron spectra generated in the decays of 140Nd and 111In.

The low-energy electron spectra generated in the decay of 140Nd have been measured using a combined electrostatic spectrometer adjusted to the 4, 7, and 35 eV instrumental resolution. In order to estimate the therapeutic potential of low-energy electrons associated with the decay of 140Nd, similar experiments have been performed with 111In. Relative Auger electron intensity ratios per decay are: 111In(K-Auger)/140Nd(K-Auger)=1.47(12), 111In(L-Auger) /140Nd(L-Auger)=1.1(4), and 111In(L-Auger [2.8-7 keV])/140Nd(L-Auger [2.8-7 keV])=0.24(11). The obtained K-Auger group intensity ratios have been compared with results of calculations. The good agreement found for the experimental and estimated values indicates that such information can be also derived using available nuclear and atomic data. The relative intensity of L-Auger electrons emitted within the 2.8-7 keV interval is higher for 140Nd by a factor of about 4 compared to 111In. As the L-Auger emission is dominating relative to that of the K-Auger group, this implicates that any potential endotherapeutic strategy using 140Nd-labelled targeting vectors requires a maximum accumulation of the endoradiotherapeutical close to the cell nucleus or the DNA of the tumour cell.

Preliminary data on biodistribution and dosimetry for therapy planning of somatostatin receptor positive tumours: comparison of (86)Y-DOTATOC and (111)In-DTPA-octreotide.

The somatostatin analogue (90)Y-DOTATOC (yttrium-90 DOTA- D-Phe(1)-Tyr(3)-octreotide) is used for treatment of patients with neuroendocrine tumours. Accurate pretherapeutic dosimetry would allow for individual planning of the optimal therapeutic strategy. In this study, the biodistribution and resulting dosimetric calculation for therapeutic exposure of critical organs and tumour masses based on the positron emission tomography (PET) tracer (86)Y-DOTATOC, which is chemically identical to the therapeutic agent, were compared with results based on the tracer commonly used for somatostatin receptor scintigraphy, (111)In-DTPA-octreotide (indium-111 DTPA- D-Phe(1)-octreotide, OctreoScan). Three patients with metastatic carcinoid tumours were investigated. Dynamic and static PET studies with 77-186 MBq (86)Y-DOTATOC were performed up to 48 h after injection. Serum and urinary activity were measured simultaneously. Within 1 week, but not sooner than 5 days, patients were re-investigated by conventional scintigraphy with (111)In-DTPA-octreotide (110-187 MBq) using an equivalent protocol. Based on the regional tissue uptake kinetics, residence times were calculated and doses for potential therapy with (90)Y-DOTATOC were estimated. Serum kinetics and urinary excretion of both tracers showed no relevant differences. Estimated liver doses were similar for both tracers. Dose estimation for organs with the highest level of radiation exposure, the kidneys and spleen, showed differences of 10.5%-20.1% depending on the tracer. The largest discrepancies in dose estimation, ranging from 23.1% to 85.9%, were found in tumour masses. Furthermore, there was a wide inter-subject variability in the organ kinetics. Residence times (tau(organs)) for (90)Y-DOTATOC therapy were: tau(liver) 1.59-2.79 h; tau(spleen) 0.07-1.68 h; and tau(kidneys) 0.55-2.46 h (based on (86)Y-DOTATOC). These data suggest that dosimetry based on (86)Y-DOTATOC and (111)In-DTPA-octreotide yields similar organ doses, whereas there are relevant differences in estimated tumour doses. Individual pretherapeutic dosimetry for (90)Y-DOTATOC therapy appears necessary considering the large differences in organ doses between individual patients. If possible, the dosimetry should be performed with the chemically identical tracer (86)Y-DOTATOC.

Lung cancer and cigarette smoking in Europe: an update of risk estimates and an assessment of inter-country heterogeneity.

Ten case-control studies have been carried out in 6 European countries to investigate the major risk factors for lung cancer. Carcinogenic effect from cigarette smoke was the most relevant interest in our study, which has included 7,609 cases of lung cancer and 10,431 controls, mainly population based. The results indicate elevated odds ratios (ORs; 23.9 among men and 8.7 among women) with attributable risks exceeding 90% for men and close to 60% for women. A large, and statistically significant, variability of the results across countries was detected after adjusting for the most common confounding variables, and after controlling, at least in part, for the instability of the ORs due to the small number of non-smokers in some of the study subsets. This pattern of lung cancer risk associated with cigarettes smoke, across different European regions, reflects inherent characteristics of the studies as well as differences in smoking habits, particularly calendar periods of starting, and it is likely to have been influenced by effect modifiers like indoor radon exposure, occupation, air pollution and dietary habits.

Production and radiochemical separation of the Auger electron emitter 140Nd.

Among the Auger electron emitters, the radiolanthanide 140Nd has some unique nuclear properties with potential for endoradiotherapeutic applications. In the present study, 140Nd was produced via the 140Ce(3He,3n) nuclear process at the FZ Jülich CV28 cyclotron, irradiating CeO2 with 3He particles of 36 MeV primary energy. Yields of about 5 MBq 140Nd per microAh were experimentally obtained. Batch yields of > 100 MBq 140Nd were reached. 140Nd was separated in 75 +/- 5% radiochemical yield using a two-step process, first by extracting the bulk of the target material according to a Ce(IV)/Nd(III) separation, then by final ion exchange purification.

Cigar and pipe smoking and lung cancer risk: a multicenter study from Europe.

BACKGROUND: Because limited information is available on the quantitative association between consumption of tobacco products other than cigarettes and lung cancer risk, we undertook a case-control study of this relationship. METHODS: We investigated lung cancer risk among smokers of cigars and/or cigarillos only and of pipes only and compared these risks with the risk of smokers of cigarettes only in a case-control study conducted in seven European areas. Our study population consisted of 5621 male case patients with lung cancer and 7255 male control subjects. Each subject or his proxy was interviewed with respect to the subject's smoking history and other risk factors for lung cancer. RESULTS: The odds ratio (OR) for smoking cigars and cigarillos only was 9.0 (95% confidence interval [CI] = 5.8-14.1), based on 43 exposed case patients and 77 exposed control subjects, and the OR for smoking a pipe only was 7.9 (95% CI = 5.3-11.8), representing 61 case patients and 129 control subjects. The OR for smoking cigarettes only was 14.9 (95% CI = 12.3-18.1), based on 4204 case patients and 3930 control subjects. A dose-response relationship was present for duration of use and cumulative consumption both for cigars and cigarillos and for pipe tobacco. An effect was also suggested for inhalation of cigar and cigarillo smoke. The dose-response relationships between lung cancer risk and either duration of smoking or average and cumulative consumption were similar for cigar and cigarillo smoking, pipe smoking, and cigarette smoking. CONCLUSION: Our results suggest that smoking of European cigars, cigarillos, and pipe tobacco might exert a carcinogenic effect on the lung comparable to that of cigarettes.

Uptake kinetics of the somatostatin receptor ligand [86Y]DOTA-DPhe1- Tyr3-octreotide ([86Y]SMT487) using positron emission tomography in non-human primates and calculation of radiation doses of the 90Y-labelled analogue.

[90Y]DOTA-DPhe1-Tyr3-octreotide ([90Y]-SMT487) has been suggested as a promising radiotherapeutic agent for somatostatin receptor-expressing tumours. In order to quantify the in vivo parameters of this compound and the radiation doses delivered to healthy organs, the analogue [86Y]DOTA-DPhe1-Tyr3-octreotide was synthesised and its uptake measured in baboons using positron emission tomography (PET). [86Y]DOTA-DPhe1-Tyr3-octreotide was administered at two different peptide concentrations, namely 2 and 100 microg peptide per m2 body surface. The latter concentration corresponded to a radiotherapeutic dose. In a third protocol [86Y]DOTA-DPhe1-Tyr3-octreotide was injected in conjunction with a simultaneous infusion of an amino acid solution that was high in l-lysine in order to lower the renal uptake of radioyttrium. Quantitative whole-body PET scans were recorded to measure the uptake kinetics for kidneys, liver, lung and bone. The individual absolute uptake kinetics were used to calculate the radiation doses for [90Y]DOTA-DPhe1-Tyr3-octreotide according to the MIRD recommendations extrapolated to a 70-kg human. The highest radiation dose was received by the kidneys, with 2.1-3.3 mGy per MBq [90Y]DOTA-DPhe1-Tyr3-octreotide injected. For the 100 microg/m2 SMT487 protocol with amino acid co-infusion this dose was about 20%-40% lower than for the other two treatment protocols. The liver and the red bone marrow received doses ranging from 0.32 to 0.53 mGy and 0.03 to 0.07 mGy per MBq [90Y]DOTA-DPhe1-Tyr3-octreotide, respectively. The average effective dose equivalent amounted to 0. 23-0.32 mSv/MBq. The comparatively low estimated radiation doses to normal organs support the initiation of clinical phase I trials with [90Y]DOTA-DPhe1-Tyr3-octreotide in patients with somatostatin receptor-expressing tumours.

PET-pharmacokinetics of 18F-octreotide: a comparison with 67Ga-DFO- and 86Y-DTPA-octreotide.

The quantitative uptake kinetics of (2-[18F]fluoropropionyl-(D)phe1)-octreotide (I), a somatostatin (SRIF) receptor-specific tracer, was measured by PET. Conventional organ biodistribution and in vivo stabilities of the tracer as well as in vivo displacement and SRIF receptor blocking were determined. The 18F-fluorinated octreotide was compared with ([67Ga]-DFO-B-succinyl-(D)phe1)-octreotide (II) and ([86Y]-DTPA-(D)phe1)-octreotide (III). Initially, 2-10 MBq of the labeled tracers were injected into male Lewis rats bearing an exocrine pancreatic islet cell tumor. PET measurements were performed dynamically between 0 and 120 min postinjection. Organ distributions were determined 5, 15, 30, 60, and 120 min postinjection. The extent of metabolic degradation was analyzed in serial blood and urine samples as well as in homogenized samples of tumor, liver, and kidney. The uptake of (I) by the tumor was rapid (maximum accumulation at 1-2 min postinjection) and high (about 0.5 +/- 0.2% ID/g), followed by a fast and continuous release with koff = 10 +/- 2. 10(-5) s-1. The tracer was found to remain intact in vivo up to 120 min postinjection. Specific binding of (I) to SRIF receptors in the adrenals, the pancreas, and the pituitary gland was demonstrated in vivo by pretreatment and displacement experiments. Compound (II) also showed a fast uptake by the tumor. Its tumor residence half-life was longer (koff = 3.0 +/- 0.5 . 10(-5) s-1). Compound (II) was also predominantly excreted intact. One hour postinjection, the remaining activity in the blood pool was found to be bound to serum proteins. Early uptake kinetics for compound (III) were also rapid but reached only half the tumor uptake of (II). Compared to (I), the release of 86Y-activity from the tumor was slower (koff = 3.1 +/- 1.3 . 10(-5) s-1). Compared to (II), compound (III) was considerably less stable in vivo. The main critical organs for (II) and (III) are kidneys and bones, whereas (I) is predominantly accumulated in the liver. The in vivo behavior of (I) closely resembles 14C-labeled octreotide. Thus, 18F-labeled octreotide may be of interest in the quantitation and investigation of in vivo properties of somatostatin receptors by PET. However, the short residence of (2-[18F]fluoropropionyl-(D)phe1)-octreotide in tumors and its hepatobiliary excretion may complicate the interpretation of abdominal tumors.

211At-methylene blue for targeted radiotherapy of disseminated melanoma: microscopic analysis of tumour versus normal tissue damage.

The present stage of our preclinical investigations of targeted radiotherapy for melanoma with 3,7-(dimethylamino)phenazathionium chloride [methylene blue (MTB)] labelled with astatine-211 (211At), an alpha-particle emitter, concerns toxicity of the treatment, as well as macro- and microscopic evaluation of its efficacy. Fragments of two human melanoma xenografts, pigmented HX118 and non-pigmented HX34 (used as a control), were implanted s.c. into nude mice subsequently treated with two doses of 211At-MTB injected i.v. Alterations in tumour growth rate were related to microscopic damage caused by 211At-MTB to the lesions, as determined by light microscopy using histopathological techniques. 211At-MTB-dependent growth inhibition of pigmented melanoma occurred either instantly or as a gradual reduction in the tumour growth rate. At a later stage, lesions that ceased to grow immediately consisted of quiescent, heavily pigmented tumour cells, as well as advanced fibrosis, and were extensively infiltrated by melanin-laden phagocytes. Large, unresorbed and often calcified necrotic deposits characterised the tumours responding gradually to the treatment. 211At-MTB remained non-toxic in normal organs. Only a relative number of small lymphocytes in the groin lymph nodes in a minority of animals was temporarily reduced, most often in conjunction with the treatment of pigmented tumours. The data demonstrated a high therapeutic effectiveness of 211At-MTB towards pigmented melanoma at the expense of negligible injury to normal tissues, and revealed that the macroscopic determination of tumour growth rate often underestimated an efficacy of the applied treatment.