Position paper on requirements for toxicological studies in the specific case of radiopharmaceuticals.

This is a position paper of the Radiopharmacy Committee of the EANM (European Association of Nuclear Medicine) addressing toxicology studies for application of new diagnostic and therapeutic radiopharmaceuticals (RP) that are not approved (i.e., not having a marketing authorization or a monograph in the European Pharmacopoeia), excluding endogenous and ubiquitous substances in humans. This paper discusses the requirements for clinical trials with radiopharmaceuticals for clinical research applications, not necessarily intended to aim at a marketing authorization. If marketing authorization is intended, scientific advice of the competent authorities is mandatory and cannot be replaced by this position paper. The position paper reflects the view of the Radiopharmacy Committee of the EANM and can be used as a basis for discussions with the responsible authorities.

Guidance on validation and qualification of processes and operations involving radiopharmaceuticals.

BACKGROUND: Validation and qualification activities are nowadays an integral part of the day by day routine work in a radiopharmacy. This document is meant as an Appendix of Part B of the EANM "Guidelines on Good Radiopharmacy Practice (GRPP)" issued by the Radiopharmacy Committee of the EANM, covering the qualification and validation aspects related to the small-scale "in house" preparation of radiopharmaceuticals. The aim is to provide more detailed and practice-oriented guidance to those who are involved in the small-scale preparation of radiopharmaceuticals which are not intended for commercial purposes or distribution. RESULTS: The present guideline covers the validation and qualification activities following the well-known "validation chain", that begins with editing the general Validation Master Plan document, includes all the required documentation (e.g. User Requirement Specification, Qualification protocols, etc.), and leads to the qualification of the equipment used in the preparation and quality control of radiopharmaceuticals, until the final step of Process Validation. CONCLUSIONS: A specific guidance to the qualification and validation activities specifically addressed to small-scale hospital/academia radiopharmacies is here provided. Additional information, including practical examples, are also available.

Quantitative [(123)I]FP-CIT pinhole SPECT imaging predicts striatal dopamine levels, but not number of nigral neurons in different mouse models of Parkinson's disease.

Single photon emission computed tomography (SPECT) using [(123)I]FP-CIT as radioligand for the dopamine transporter has become a widely used tool to monitor the integrity of the nigrostriatal dopaminergic projection in Parkinson's disease (PD). Previous studies with pinhole SPECT in small animals have demonstrated that the striatal [(123)I]FP-CIT binding indeed correlates with the striatal dopamine transporter protein level. It is unclear, however, if there is a stable relationship between the striatal [(123)I]FP-CIT binding and other functionally important parameters of the nigrostriatal system, such as the striatal dopamine levels and the number of dopaminergic neurons in the substantia nigra. To assess this question experimentally, we studied two different mouse models of PD, namely a mild 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication paradigm, to model mild nigrostriatal damage and the intrastriatal 6-hydroxydopamine paradigm to model more advanced nigrostriatal damage. Our data demonstrate that the striatal [(123)I]FP-CIT binding measured by SPECT in vivo precisely predicts the striatal dopamine concentrations, but does not necessarily correlate with the nigral dopaminergic cell number. Thus, the present work underscores that FP-CIT SPECT does only allow judging the integrity of the striatal dopaminergic nerve terminals, but not the nigral dopaminergic cells in PD. This finding may have significant impact on the use of [(123)I]FP-CIT SPECT as a surrogate marker for clinical trials aimed at measuring neuroprotection.

Scintigraphy with 99mTc-labeled heat-altered erythrocytes in diagnosing hyposplenia: prospective comparison to 99mTc-labeled colloids and colour-coded duplex ultrasonography.

AIM: Ultrasound may be a cheap alternative to scintigraphic determination of splenic function. We directly compared nanocolloid scintigraphy (NS), scintigraphy with heat-altered erythrocytes (ES), and colour-coded Doppler sonography (DS) in patients with chronic inflammatory bowel disease (CIBD). PATIENTS, METHODS: 35 patients were included into the study. Clearance rates were determined in ES, spleen/liver ratios (SLR) were measured scintigraphically in ES/NS. In DS, spleen size, echogenicity, and vascular resistance indices (RI) were determined. The results were compared to each other, to the clinical activity scores for CIBD, and to the course of the disease. RESULTS: Based on the blood erythrocyte clearance serving as standard, patients had a good (19 patients), impaired (5), or missing splenic function (11). There was a good correlation of the clearance to SLR in ES (0.63, p < 0.01). The 10 min / 45 min ES clearance showed a high correlation (Spearman-Rho 0.87, p < 0.01). The SLR in ES at 2, 5, 10 and 45 min also correlated well with each other (Spearman-Rho > 0.9, p < 0.01; SLR > 3.45 normal splenic function, SLR < 1.22 indicated hyposplenia). There were no correlations between the results of NS, DS, Howell-Jolly-bodies, or clinical parameters. Only ES and the erythrocyte clearance correlated well. Howell-Jolly-Bodies detected 1 of 11 patients with hyposplenia while false-positive in 4. CONCLUSION: Ultrasound and colloid scintigraphy show a low correlation with clearance of heat-altered erythrocytes. Only ES shows a good correlation in patients with CIBD. The clearance at 10 min already reliably determines splenic function. SLR may be determined after 10 minutes and is predictive of normal function if above 3.45 while SLR < 1.2 indicated hyposplenia.

[Combination of radiological and nuclear medical imaging in animals: an overview about today's possibilities]. / Kombinierte radiologische und nuklearmedizinische Bildgebung in Tierexperimenten: Ein Uberblick über die aktuellen Möglichkeiten.

Molecular imaging of small animals has made considerable progress in the last years. Various research fields are interested in imaging small animals due to the lower numbers of animals per experiment. This has advantages with respect to financial, ethical and research aspects. Non-invasive imaging allows examination of one animal several times during the same experiment. This makes it possible to follow a pathological process in the same animal over time. However, the radiological methods used such as magnetic resonance imaging or computed tomography as well as the nuclear medicine methods such as single photon emission computed tomography or positron emission tomography suffer from disadvantages. Molecular aspects are limited in the radiological methods while anatomical localization is difficult in nuclear medicine. The fusion of these methods leads to additional information. This review shows today's possibilities with their advantages as well as disadvantages.

[Molecular imaging of apoptosis in cardiovascular diseases]. / Molekulare Bildgebung der Apoptose bei kardiovaskulären Erkrankungen.

Molecular imaging of functional parameters such as apoptosis (programmed cell death) in vivo opens new possibilities in clinical diagnostic and scientific research. Especially in the case of cardiovascular diseases that are mainly responsible for both morbidity and mortality in Western industrial nations, innovative non-invasive examination strategies are necessary for early diagnosis of these diseases. Since apoptosis unlike necrosis is present even after minor alterations of the microenvironment of cells and has been shown to be involved in a large number of cardiovascular diseases, there are currently several experimental studies underway with the goal of imaging apoptosis in vivo. The review discusses the basics of apoptosis in myocardial infarction, myocarditis, atherosclerosis, restenosis after angioplasty and stent implantation, currently used imaging techniques, achieved results, and future possibilities for molecular imaging of apoptosis.

What is the best pre-therapeutic dosimetry for successful radioiodine therapy of multifocal autonomy?

PURPOSE: Dose calculation for radioiodine therapy (RIT) of multifocal autonomies (MFA) is a problem as therapeutic outcome may be worse than in other kinds of autonomies. We compared different dosimetric concepts in our patients. PATIENTS, METHODS: Data from 187 patients who had undergone RIT for MFA (Marinelli algorithm, volumetric compromise) were included in the study. For calculation, either a standard or a measured half-life had been used and the dosimetric compromise (150 Gy, total thyroid volume). Therapeutic activities were calculated by 2 alternative concepts and compared to therapeutic success achieved (concept of TcTUs-based calculation of autonomous volume with 300 Gy and TcTUs-based adaptation of target dose on total thyroid volume). RESULTS: If a standard half-life is used, therapeutic success was achieved in 90.2% (hypothyroidism 23,1%, n = 143). If a measured half-life was used the success rate was 93.1% (13,6% hypothyroidism, n = 44). These differences were statistically not significant, neither for all patients together nor for subgroups eu-, hypo-, or hyperthyroid after therapy (ANOVA, all p > 0.05). The alternative dosimetric concepts would have resulted either in significantly lower organ doses (TcTUs-based calculation of autonomous volume; 80.76 +/- 80.6 Gy versus 125.6 +/- 46.3 Gy; p < 0.0001) or in systematic over-treatment with significantly higher doses (TcTUs-adapted concept; 164.2 +/- 101.7 Gy versus 125.6 +/- 46.3 Gy; p = 0.0097). CONCLUSIONS: TcTUsbased determination of the autonomous volume should not be performed, the TcTUs-based adaptation of the target dose will only increase the rate of hypothyroidism. A standard half-life may be used in pre-therapeutic dosimetry for RIT of MFA. If so, individual therapeutic activities may be calculated based on thyroid size corrected to the 24h ITUs without using Marinelli's algorithm.

Development and clinical application of peptide-based radiopharmaceuticals.

Peptide-based radiopharmaceuticals have been introduced into clinical work more than a decade ago. The first and most successful imaging agent to date is the somatostatin analog octreotide. It is used for somatostatin receptor scintigraphy and also receptor-mediated peptide-radiotherapy of neuroendocrine tumors. For in vivo use as radiopharmaceutical, the natural peptide is modified in order to enhance the metabolic stability and to allow stable labeling with a so-called residualizing label. This means, that a radiometal chelator complex bound to a modified peptide stable in serum is internalized into the target cells via a specific receptor. The peptide then undergoes lysosomal degradation leaving the radiometal-chelator complex trapped inside the cell, leading to a high target to background ratio. The successful development of new radiopeptides is thus dependent on modifications of a given natural peptide while preserving the binding affinity for the target receptor(s) at the same time. Other peptides than somatostatin are under development for use as radiopeptides such as Minigastrin, GLP-1, VIP, Substance P, or Neurotensin. Some show very favorable results in clinical trials, like Minigastrin for example. Furthermore, there is increasing interest in peptide-binding sites other than the "classical" receptors for regulatory peptides specifically over-expressed by (neuroendocrine) tumors. In this paper, we provide an overview of the biochemical and radiochemical aspects of radiopeptide development, the current state of clinical use of radiopeptides for diagnosis and therapy of tumors, the current state of development of new compounds, and future developments.

99mTc-labeling and in vitro and in vivo evaluation of HYNIC- and (Nalpha-His)acetic acid-modified [D-Glu1]-minigastrin.

Gastrin/CCK-2 receptors are overexpressed in a number of tumors such as medullary thyroid cancer (MTC) and small cell lung cancer (SCLC). Recently [D-Glu1]-minigastrin (MG) has been radiolabeled with 131I, 111In, and 90Y and evaluated in patients. This study describes the labeling and evaluation of MG with technetium-99m using two different labeling approaches: HYNIC as bifunctional coupling agent and (Nalpha-His)Ac as tridentate ligand for 99mTc(CO3) labeling. Labeling was perfomed at high specific activities using Tricine and EDDA as coligands for HYNIC-MG and [99mTc(OH2)3(CO)3]+ for (Nalpha-His)Ac-MG. Stability experiments were carried out by reversed phase HPLC analysis in PBS, serum, histidine, and cysteine solutions, as well as rat liver and kidney homogenates. Receptor binding and internalization experiments were performed using CCK-2 receptor positive AR42J rat pancreatic tumor cells. Biodistribution experiments were carried out in nude mice carrying AR42J tumors by injection of 99mTc-labeled peptide with or without coinjection of 50 microg of minigastrin I human (MGh). HYNIC-MG and (Nalpha-His)Ac-MG could be radiolabeled at high specific activities (>1 Ci/micromol). For HYNIC-MG, high labeling yields (>95%) were achieved using Tricine and EDDA as coligands. Stability experiments of all 99mTc-labeled conjugates revealed a high stability of the label in PBS and serum as well as toward challenge with histidine and cysteine. Incubation in kidney homogenates resulted in a rapid degradation of all conjugates with <10% intact peptide after 60 min at 37 degrees C, with no considerable differences between the radiolabeled conjugates; a somewhat lower degradation rate was seen in liver homogenates. Protein binding varied considerably with lowest levels for 99mTc-EDDA/HYNIC-MG. Competition experiments of unlabeled conjugates on AR42J membranes versus [125I-Tyr12]-gastrin I showed high CCK-2 receptor affinity for all conjugates under study. Internalization behavior was very rapid for all radiolabeled conjugates in the order of 99mTc-(Nalpha-His)Ac-MG > 99mTc-EDDA/HYNIC-MG > 99mTc-Tricine/HYNIC-MG. In tumor-bearing nude mice the highest tumor-uptake was observed with 99mTc-EDDA/HYNIC-MG (8.1%ID/g) followed by 99mTc-Tricine/HYNIC-MG (2.2%ID/g) and 99mTc-(Nalpha-His)Ac-MG (1.2%ID/g) which correlated with kidney uptake (101.0%ID/g, 53.8%ID/g, 1.8%ID/g respectively). In this series of compounds 99mTc-EDDA/HYNIC-MG with its very high tumor/organ ratios except for kidneys seems to be the most promising agent to target CCK-2 receptors. Despite promising properties concerning receptor binding, internalization, and in vitro stability, 99mTc-(Nalpha-His)Ac-MG showed low tumor uptake in vivo.

Erythropoietin: a candidate compound for neuroprotection in schizophrenia.

Erythropoietin (EPO) is a candidate compound for neuroprotection in human brain disease capable of combating a spectrum of pathophysiological processes operational during the progression of schizophrenic psychosis. The purpose of the present study was to prepare the ground for its application in a first neuroprotective add-on strategy in schizophrenia, aiming at improvement of cognitive brain function as well as prevention/slowing of degenerative processes. Using rodent studies, primary hippocampal neurons in culture, immunohistochemical analysis of human post-mortem brain tissue and nuclear imaging technology in man, we demonstrate that: (1) peripherally applied recombinant human (rh) EPO penetrates into the brain efficiently both in rat and humans, (2) rhEPO is enriched intracranially in healthy men and more distinctly in schizophrenic patients, (3) EPO receptors are densely expressed in hippocampus and cortex of schizophrenic subjects but distinctly less in controls, (4) rhEPO attenuates the haloperidol-induced neuronal death in vitro, and (4) peripherally administered rhEPO enhances cognitive functioning in mice in the context of an aversion task involving cortical and subcortical pathways presumably affected in schizophrenia. These observations, together with the known safety of rhEPO, render it an interesting compound for neuroprotective add-on strategies in schizophrenia and other human diseases characterized by a progressive decline in cognitive performance.

LeukoScan for imaging infection in different clinical settings: a retrospective evaluation and extended review of the literature.

PURPOSE: The aim of the current study was to determine the overall diagnostic accuracy of Tc-99m-labeled antigranulocyte monoclonal antibody Fab' fragments (LeukoScan) for the routine detection of bone and soft tissue infections in a retrospective evaluation. PATIENTS AND METHODS: 138 patients (63 men, 75 women; mean age, 58.29 +/- 25.38 years) with fever of unknown origin and possible endocarditis (n = 59), infection of arthroplastic joints (n = 20), arthritis (n = 16), peripheral (n = 15) and central bone infections (n = 14), soft tissue infection (n = 6), appendicitis (n = 4), pericarditis (n = 2), or vascular graft infection (n = 2) underwent imaging after injection of 555 to 925 MBq (15 to 25 mCi) Tc-99m-labeled antigranulocyte monoclonal antibody Fab' fragments (LeukoScan). RESULTS: True-positive results were found in 63 of 81 lesions. The overall sensitivity and specificity were 76% and 84%, respectively. In arthritis, seven of seven foci could be detected, whereas false-negative results were found in infections of the femoral bone in three of nine lesions and in periprosthetic infections of long bones in three of eight lesions. Good results were found in five of six soft-tissue infections, in four of six patients with endocarditis, in three of four atypical cases of appendicitis, in two of two infected vascular grafts, and in one of one patient with pericarditis. Subacute and chronic infections of the spine always showed photopenic areas in eight of eight patients. If photopenic lesions were included as diagnostic criteria, the sensitivity and specificity were 88% and 67%, respectively. CONCLUSIONS: Tc-99m-labeled antigranulocyte monoclonal antibody Fab' fragments can be used for imaging acute infections of peripheral bones and soft tissues. False-negative results are likely in patients with chronic infections. Sensitivity can be increased while decreasing specificity by including photopenic lesions in the spine as diagnostic criteria for localizing disease.

Radioiodination of monoclonal antibodies, proteins and peptides for diagnosis and therapy. A review of standardized, reliable and safe procedures for clinical grade levels kBq to GBq in the Göttingen/Marburg experience.

Simple and reliable methodologies for radioiodination of proteins and peptides are described. The labeling systems are easy to assemble, capable of radioiodinating any protein or, with slight modifications, also peptide (molecular mass 1000-300,000) from kBq to GBq levels of activity for use in diagnosis and/or therapy. Furthermore, the procedures are feasible in any nuclear medicine department. Gigabecquerel amounts of activity can be handled safely. The most favored iodination methodology relies on the lodogen system, a mild oxidating agent without reducing agents. Thus, protein degradation is minimized. Labeling yields are between 60 and 90%, and immunoreactivities remain > or = 85%. Other radioiodination methods (chloramine-T, Bolton-Hunter) are described and briefly discussed.

Follow-up of perfusion defects in pulmonary perfusion scanning after pulmonary embolism: are we too careless?

Persisting perfusion defects may still be found in pulmonary perfusion scintigraphy months or years after pulmonary embolism. The aim of this study was to investigate the rate of persisting perfusion defects and the pattern of scintigraphic follow-up of patients after pulmonary embolism. Only those patients were included into our study who received pulmonary perfusion scintigraphy between 1991 and 1999, and who had perfusion defects including at least one whole segment. These perfusion defects were considered as persisting perfusion defects if unchanged over at least 1 year. From 3640 patients examined, 451 (12.4%) had perfusion defects meeting the criteria of this study. Of those, 129 (28.6%) received a scintigraphic follow-up. In 62 patients (48.1%), a reperfusion of the defects was found. In 38 patients (29.5%), the defects persisted within a follow-up period of up to 12 weeks. However, no pulmonary perfusion scintigraphy was performed thereafter. Out of the 129 patients receiving a scintigraphic follow-up, only 29 (22.5%) had a follow-up over more than 1 year, 19 of those had persisting perfusion defects. It is concluded that our data show an inadequate scintigraphic follow-up of patients with pulmonary embolism which may lead to unnecessary anticoagulant treatment if persisting perfusion defects are misinterpreted as fresh pulmonary embolism. In many cases, there was no further follow-up even if reperfusion of the defects was lacking in early follow-up.

18F-FDG hybrid PET in patients with suspected spondylitis.

This study investigated the value of fluorine-18 2'-deoxy-2-fluoro- D-glucose (FDG) imaging with a double-headed gamma camera operated in coincidence (hybrid PET) detection mode in patients with suspected spondylitis. Comparison was made with conventional nuclear medicine imaging modalities and magnetic resonance imaging (MRI). Sixteen patients with suspected spondylitis (nine male, seven female, mean age 59 years) prospectively underwent FDG hybrid PET (296 MBq) and MRI. For intra-individual comparison, the patients were also imaged with technetium-99m methylene diphosphonate (MDP) (555 MBq) ( n=13) and/or gallium-67 citrate (185 MBq) ( n=11). For FDG hybrid PET, two or three transverse scans were performed. Ratios of infected (target) to non-infected (background) (T/B) vertebral bodies were calculated. MR images were obtained of the region of interest. Patients found positive for spondylitis with MRI and/or FDG hybrid PET underwent surgical intervention and histological grading of the individual infected foci. Twelve out of 16 patients were found to be positive for spondylitis. Independent of the grade of infection and the location in the spine, all known infected vertebrae ( n=23, 9 thoracic, 12 lumbar, 2 sacral) were detected by FDG hybrid PET. T/B ratios higher than 1.45+/-0.05 (at 1 h p.i.) were indicative of infectious disease, whereas ratios below this value were found in cases of degenerative change. FDG hybrid PET was superior to MRI in patients who had a history of surgery and suffered from a high-grade infection in combination with paravertebral abscess formation ( n=2; further computed tomography was needed) and in those with low-grade spondylitis ( n=2, no oedema) or discitis ( n=2, mild oedema). False-positive 67Ga citrate images ( n=5: 2 spondylodiscitis, 1 aortitis, 1 pleuritis, 1 pulmonary tuberculosis) and 99mTc-MDP SPET ( n=4: 1 osteoporosis, 2 spondylodiscitis, 1 fracture) were equally well detected by FDG hybrid PET and MRI. No diagnostic problems were seen in the other patients ( n=5). In this study, FDG hybrid PET was superior to MRI, 67Ga citrate and (99m)Tc-MDP, especially in patients with low-grade spondylitis (as compared with MRI), adjacent soft tissue infections (as compared with 67Ga citrate) and advanced bone degeneration (as compared with 99mTc-MDP).

(99m)Tc-E-selectin binding peptide for imaging acute osteomyelitis in a novel rat model.

INTRODUCTION: In the present study, (99m)Tc-radiolabelled E-selectin binding peptide ((99m)Tc-IMP-178) was investigated for its potential to image acute pyogenic osteomyelitis in a new animal model. Intraindividual comparisons were performed using an irrelevant peptide ((99m)Tc-IMP-100) to demonstrate specificity. METHODS: An acute pyogenic osteomyelitis was induced by injecting 0.05 ml of 5% sodium morrhuate and 5x10(8) CFU of Staphylococcus aureus into the medullary cavity of the right tibia in 16 rats. Sixteen additional rats served as untreated controls. Whole-body imaging of pyogenic (n=4) and untreated (n=4) animals was performed continuously during the first 8 h (12 MBq i.v. of (99m)Tc-IMP-178 and (99m)Tc-IMP-100 for control), and one further single image was acquired after 16 h p.i. Tissue biodistribution studies were performed in 12 rats with an acute pyogenic osteomyelitis and in 12 untreated rats 1, 4 and 24 h after injection. Data of the histological/radiological and haematological investigations were obtained in all animals. RESULTS: Histopathologically, 15 of 16 treated rats (93%) developed an acute pyogenic osteomyelitis showing a major infiltration of the bone marrow by polymorphonuclear leukocytes as well as the formation of sequestra. Haematologically, the number of leukocytes increased by 100%, the lymphocytes by 11% and the granulocytes decreased by 39%. After i.v. injection, (99m)Tc-IMP-178 rapidly cleared from the body resulting in good scintigraphic target-to-background (T/B) ratios. The highest uptake of the tracer in the pyogenic bone was observed at 60 min p.i. (0.43+/-0.02% ID.g-1 for (99m)Tc-IMP-178 and 0.30+/-0.02% ID.g-1 for (99m)Tc-IMP-100), resulting in a higher osteomyelitis-to-healthy collateral ratio with T/B of 2.40+/-0.65 ((99m)Tc-IMP-178) compared with 1.85+/-0.48 ((99m)Tc-IMP-100). No adverse reactions were seen after injection of (99m)Tc-IMP-178. CONCLUSIONS: (99m)Tc-IMP-178 allows imaging of an acute osteomyelitic lesions, presumably by interaction of (99m)Tc-IMP-178 with activated upregulated vascular endothelium.

Imaging tumors with peptide-based radioligands.

Regulatory peptides are small, readily diffusable and potent natural substances with a wide spectrum of receptor-mediated actions in humans. High affinity receptors for these peptides are (over-) expressed in many neoplasms, and these receptors may represent, therefore, new molecular targets for cancer diagnosis and therapy. This review aims to give an overview of the peptide-based radiopharmaceuticals which are presently already commercially available or which are in advanced stages of their clinical testing so that their broader availability is anticipated soon. Physiologically, these peptides bind to and act through G protein-coupled receptors in the cell membrane. Historically, somatostatin analogs are the first class of receptor binding peptides having gained clinical application. 111In-DTPA-[D-Phe1]-octreotide is the first and only radiopeptide which has obtained regulatory approval in Europe and the United States to date. Extensive clinical studies involving several thousands of patients have shown that the major clinical application of somatostatin receptor scintigraphy is the detection and the staging of gastroenteropancreatic neuroendocrine tumors (carcinoids). In these tumors, octreotide scintigraphy is superior to any other staging method. However, its sensitivity and accuracy in other, more frequent neoplasms is limited. Radiolabeled vasoactive intestinal peptide (VIP) has been shown to visualize the majority of gastrointestinal adenocarcinomas, as well as some neuroendocrine tumors, including insulinomas (the latter being often missed by somatostatin receptor scintigraphy). Due to the outstanding diagnostic accuracy of the pentagastrin test in detecting the presence, persistence, or recurrence of medullary thyroid cancer (MTC), we postulated the expression of the corresponding (ie. cholecystokinin [CCK-] -B) receptor type in human MTC. This receptor is also widely expressed on human small-cell lung cancer. Indeed, 111In-labeled DTPA derivatives of gastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and patients. A variety of further peptide-based radioligands, e.g. among many others, gastrin-releasing peptide/bombesin, neurotensin, substance-P, pan-somatostatin (somatostatin derivatives which bind to all five receptor subtypes) or glucagon-like peptide-1 (glp-1) analogs (the latter for the specific detection of insulinomas), is currently under development. Summarizing, radiolabeled regulatory peptides have opened new horizons in nuclear oncology for diagnosis (and potential internal radionuclide therapy). Future work will probably reveal a multitude of novel potentially clinically useful peptide-based radioligands.