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FAP-targeted radiopharmaceuticals represent a breakthrough in cancer imaging and a viable option for therapeutic applications. OncoFAP, an ultra-high affinity ligand of FAP, has been recently discovered and clinically validated for PET imaging procedures in patients with solid malignancies. While more and more clinical validation is becoming available, the need for scalable and robust procedures for the preparation of this new class of radiopharmaceuticals continues to increase. In this article, we present the development of automated radiolabelling procedures with FASTlab 2 for the preparation of OncoFAP-based radiopharmaceuticals for cancer imaging and therapy. A new series of [68Ga]Ga-OncoFAP, [177Lu]Lu-OncoFAP and [18F]AlF-OncoFAP was produced with high-yields. Chemical and biochemical characterization after radiolabelling confirmed excellent stability, retention of high affinity for FAP and absence of radiolysis by-products. The in vivo biodistribution of [18F]AlF-OncoFAP-NOTA, a candidate for PET imaging procedures in patients, was assessed in mice bearing FAP-positive solid tumours. The product showed rapid accumulation in solid tumours, with an average of 6.6% ID/g one hour after systemic administration and excellent tumour-to-healthy organs ratio. We have established methodologies to efficiently produce an OncoFAP-based radiotheranostic pair in which [68Ga]Ga-OncoFAP-DOTAGA is used as a companion diagnostic of the targeted therapeutic agent [177Lu]Lu-OncoFAP-DOTAGA Objectives: We have developed simple, quick, safe and robust synthetic procedures for the preparation of theranostic OncoFAP-compounds based on Gallium-68, Lutetium-177 and Alluminium-Fluoride-18 using the commercially available FASTlab 2 synthesis module.

To evaluate the reproducibility of cerebral adenosine AEight healthy male volunteers were enrolled. Dynamic 90 min PET scans were performed twice at the same time of the day to avoid the effect of diurnal variation. Subjects refrained from caffeine from 12 h prior to scanning, and serum caffeine was measured before radioligand injection. Arterial blood was sampled repeatedly during scanning and the fraction of the parent compound in plasma was determined. Total distribution volume (VRegional time-activity curves were well described by 2-TCM models. Estimation of VIn this study, moderate test-retest reproducibility and large inter-subject differences were observed with [UMIN000030040.

Background: In the last decade, several strategies emerged for the 18F-fluorination of arenes not amenable to aromatic nucleophilic substitution. However, most struggle to be translated efficiently into daily routine or lack multicenter evaluation. Presumably due to some practical drawbacks initially reported, ruthenium-mediated 18F‑deoxyfluorination has also remained a dormant radiolabeling strategy. Aims: To try to overcome some of the practical drawbacks of ruthenium-mediated 18F‑deoxyfluorination that may be preventing this technique from being widely used, an optimized, and straightforward approach was developed. With this, we aim to stimulate a broader application of this strategy to clinically relevant PET tracers throughout radiochemistry laboratories. Methods: To facilitate [18F]fluoride washing/drying procedures, enhance efficiency, reduce precursor amount, and replace the need for non-commercial additives or different solvent mixtures throughout the radiolabeling process, several modifications to the original report were evaluated. The improved method was then used for 18F-labeling clinically relevant molecules and was easily automated. Results and Conclusion: The improved procedure overcame previously known hurdles and now allows faster and practical translation to clinical settings. This enhanced method reliably yielded 5‑[18F]fluoro-tryptophan, [18F]atorvastatin, or [18F]MC225 in 28% ± 16% (d.c.) with molar activity up to 100 GBq.µmol-1. Additionally, this procedure showed the possibility of direct fluorination with aqueous [18F]fluoride.

Novel radiopharmaceuticals for the detection of tumors and their metastases may be of clinical interest if they are more tumor selective than F-18-FDG. Increased glucose metabolism of inflammatory tissues is the main source of false-positive F-18-FDG PET findings in oncology. Methods: We compared the biodistribution of 4 PET tracers (2 sigma-receptor ligands, C-11-choline, and C-11-methionine) with previously published biodistribution data of 3'-deoxy-3'-F-18-fluorothymidine (F-18-FLT) and of F-18-FDG in the same animal model. The model consisted of male Wistar rats that bore tumors (C6 rat glioma in the right shoulder) and also had sterile inflammation in the left calf muscle (induced by injection of 0.1 mL of turpentine). Twenty-four hours after turpentine injection, the rats received an intravenous bolus of PET tracer (approximately 30 MBq in the case of F-18 and 74 MBq for C-11). Results: F-18-FDG showed the highest tumor-to-muscle ratio of all radiopharmaceuticals (13.2 +/- 3.0, mean +/- SD), followed at a large distance by the sigma-1 ligand C-11-SA4503 (5.1 +/- 1.7), F-18-FLT (3.8 +/- 1.3), the non-subtype-selective or-ligand F-18-FE-SA5845 (3.3 +/- 1.5), C-11-choline (3.1 +/- 0.4), and C-11-methionine (2.8 +/- 0.3). sigma-Ligands and 18F-FLT were relatively tumor selective (F-18-FE-SA5845, greater than 30-fold; C-11-SA4503 and F-18-FLT, greater than 10-fold). The tumor selectivity of C-11-methionine was only slightly better than that of F-18-FDG. C-11-Choline showed equal uptake in tumor and inflammation. All tracers were avidly taken up by proliferative tissue (small intestine, bone marrow). High physiologic uptake of some compounds was observed in brain, heart, lung, pancreas, spleen, and salivary gland. Conclusion: sigma-Ligands and F-18-FLT were more tumor selective than F-18-FDG, C-11-choline, or C-11-methionine in our animal model. However, these novel radiopharmaceuticals were less sensitive than were the established oncologic tracers.

Prostate cancer is known for its difficulties in preoperative staging of pelvic lymph nodes by conventional imaging techniques. Thus, a histopathologic examination of the pelvic lymphadenectomy specimen is mandatory for patients at risk for metastatic disease. The aim of this study was to evaluate the strength and accuracy of C-11-choline PET in preoperative noninvasive staging of pelvic lymph nodes in prostate cancer. Methods: In a prospective study we examined 67 consecutive patients with histologically proven prostate cancer with C-11-choline PET. The results of PET were compared with the results of histology of the pelvic lymph nodes and with the follow-up data. Conventional axial imaging was routinely performed using MRI or CT. The sensitivity, specificity, and accuracy of C-11-choline PET were calculated. Results: Fifteen patients had histologically proven lymph node metastases. C-11-Choline PET was true-positive in 12 of 15 patients and false-negative in 3 patients. Fifty-two patients had no lymph node metastases. C-11-Choline PET was true-negative in 50 of 52 patients and false-positive in 2 patients. We calculated a sensitivity of C-11-choline PET for staging metastatic lymph node disease of 80%, a specificity of 96%, and an accuracy of 93%. Next, C-11-choline PET detected solitary extraregional lymph node metastases in 5 of 12 patients with nodal metastases. Conclusion: This study showed that C-11-choline PET is sensitive and accurate in preoperative staging of pelvic lymph nodes in prostate cancer.

The aim of this study was to determine if the brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[F-18]fluorobenzamido]ethylpiperazine ([F-18]MPPF), a radioligand for the imaging of 5-HT1A receptors, is influenced by the action of P-glycoprotein. Anesthetized male Wistar rats were injected i.v. with the 5-HT1A receptor antagonist [F-18]MPPF (2 MBq, S.A. > 110 TBq/mmol) after treatment with saline (controls) or with the 5-HT1A receptor antagonist 1-(2'-methoxyphenyl)-4-[4-(2-phtalimido)butyl]piperazine (NAN-190) (2.5 mg/kg i.v.). After 60 min, the animals were sacrificed and 13 areas of the brain were dissected for ex vivo gamma counting. The regional distribution of radioactivity was also assessed in brain slices using a storage phosphor system. Modulation of P-glycoprotein was achieved by injection of cyclosporin A (50 mg/kg) 30 min prior to injection of [F-18]MPPF. The distribution of F-18-derived radioactivity corresponded to regional 5-HT1A receptor density as known from autoradiography. Modulation of P-glycoprotein with cyclosporin A caused a 5- to 10-fold increase in the uptake of [F-18]MPPF. Tissue/cerebellum ratios in the brain correlated with receptor densities determined by in vitro autoradiography. Measurements of plasma radioactivity showed that the increased brain uptake of [F-18]MPPF is partially due to a rise in ligand delivery after treatment with cyclosporin A (area under the curve, AUC, increased by a factor of 1.8). Biodistribution experiments in wild type and mdr1a(-/-) knockout mice confirmed that [F-18]MPPF is a substrate for P-glycoprotein. (C) 2000 Elsevier Science B.V. All rights reserved.

Serotonin-1A (5-hydroxytryptamine-1A [5-HT1A]) receptors have been reported to play an important role in the pathophysiology of a variety of psychiatric and neurodegenerative disorders. Animal experiments have shown that 4-(2'-methoxyphenyl)-1-[2'-(N-2 " -pyridinyl)-p-[F-18]fluorobenzamido]ethylpiperazine ([F-18]MPPF) may be suitable for 5-HT1A receptor imaging in humans. The aim of this study was to determine if [F-18]MPPF can be used for the quantitative analysis of 5-HT1A receptor densities in brain regions of healthy human volunteers. Methods: [O-15]H2O perfusion scanning was performed before intravenous injection of [F-18]MPPF to obtain anatomic information. Cerebral radioactivity was monitored using a PET camera. Plasma metabolites of [F-18]MPPF were determined by high-performance liquid chromatography. Binding potentials were calculated using the metabolite-corrected arterial input function and a linear graphic method (Logan-Patlak analysis). Results: The highest levels of radioactivity were observed in the medial temporal cortex, especially in the hippocampal area. In contrast, the cerebellum and basal ganglia showed low uptake of F-18, in accordance with known 5-HT1A receptor distribution. The calculated binding potentials correlated well with literature values for 5-HT1A receptor densities. The binding potentials for [F-18]MPPF were 4-6 times lower than those that have been reported for [carbonyl-C-11]-(N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl) cyclohexane-carboxamide (WAY 100635), indicating that [F-18]MPPF has a lower in vivo affinity for 5-HT1A receptors. Conclusion: These results confirm that [F-18]MPPF can be used for the quantitative analysis of 5-HT1A receptor distribution in the living human brain. The:rapid dissociation from the receptor makes this ligand a possible candidate to monitor changes in endogenous serotonin levels.

The agonist radioligand N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-[C-11]-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide ([C-11]formoterol) was synthesised in order to test its ability to visualise pulmonary beta(2)-adrenoceptors in vivo, with positron emission tomography (PET). Formoterol was labelled via reaction of a dibenzyl-protected precursor with [C-11]CH3I. Subsequent deprotection with Pd/C and H-2 yielded [C-11]formoterol in 5-15% (corrected for decay) and the specific activity ranged from 5.5-22.2 TBq mmol(-1) (150-600 Ci mmol(-1)), 60-70 min after end of bombardment. Biodistribution studies with [C-11]formoterol were performed in male Wistar rats which were either untreated or predosed with (D,L)-propranolol hydrochloride (2.5 mg kg(-1), beta-adrenoceptor antagonist), erythro-DL-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol hydrochloride (ICI 118551, 0.15 mg kg(-1), beta(2)-adrenoceptor antagonist), isoprenaline (15 mg kg(-1), non-subtype selective beta-adrenoceptor agonist) or (+/-)-(2-hydroxy-5-[2-((2-hydroxy-3-(4-((1-methyl-4-trifluoromethyl)1 H-imidazol-2-yl-)phenoxy)propyl)amino)et sulfonate (CGP 20712A, 0.15 mg kg(-1), beta(1)- adrenoceptor antagonist). Lungs, heart, liver and plasma were analysed for radioactive metabolites. The kinetics of [C-11]formoterol in the lungs of male Wistar rats were investigated by means of a dynamic PET study. The biodistribution studies showed significant specific binding in tissues known to contain beta(2)-adrenoceptors (lungs, spleen, and heart). Binding in these organs was blocked by ICI 118551 and isoprenaline, but not by CGP 20712A. [C-11]Formoterol was rapidly metabolised in rats but lungs and heart did not substantially take up the labelled metabolites. The binding of [C-11]formoterol in various tissues of rats is consistent with the beta(2)-selectivity of formoterol. Whether [C-11]formoterol selectively binds to the high affinity state of beta(2)-adrenoceptors remains to be elucidated. [C-11]Formoterol is potentially useful for studying beta(2)-adrenoceptors with PET and this radioligand may provide new insights in the mechanisms underlying prolonged sympathomimetic action. (C) 1998 Elsevier Science B.V. All rights reserved.

S-1'-[F-18]fluorocarazolol was administered to healthy volunteers to assess its potential for noninvasive measurement of regional pulmonary and myocardial beta-adrenoceptor densities. Methods: High-specific activity fluorocarazolol was intravenously injected on two separate occasions within a 1-wk interval. The initial injection was without pretreatment, but before the second injection, the volunteers either inhaled salbutamol (2 x 200 mu g aerosol) or they ingested pindolol (3 x 5 mg during a 12-hr interval). Twenty-eight PET time frames of 31 planes were acquired over a period of 60 min after each injection. Blood samples were drawn and analyzed for the presence of fluorocarazolol and radioactive metabolites. Results: Uptake of fluorocarazolol in the target tissues was hardly affected by salbutamol but was strongly depressed by pindolol. Pulmonary and myocardial tissue-to-plasma concentration ratios of fluorocarazolol reached plateau values of 11.6 +/- 0.6 (lungs) and 18.1 +/- 1.0 (heart) at 45-50 min postinjection. These values were reduced to 2.0 +/- 0.4 and 2.0 +/- 0.6 after treatment with pindolol. Conclusion: These data indicate that: 1. Pulmonary and myocardial uptake of radioactivity after intravenous administration of S-1'-[F-18]fluorocarazolol represents radioligand binding to beta-adrenoceptors. 2. Pulmonary binding occurs mainly in alveoli rather than in airway smooth muscle under these conditions. 3. Binding kinetics do not preclude quantification of receptors with compartment models.

Increased glucose metabolism of inflammatory tissues is the main source of false-positive F-18-FDG PET findings in oncology. It has been suggested that radiolabeled nucleosides might be more tumor specific. Methods: To test this hypothesis, we compared the biodistribution of 3'-deoxy-3'-F-18-fluorothymidine (FLT) and F-18-FDG in Wistar rats that bore tumors (C6 rat glioma in the right shoulder) and also had sterile inflammation in the left calf muscle (induced by injection of 0.1 mL of turpentine). Twenty-four hours after turpentine injection, the rats received an intravenous bolus (30 MBq) of either F-18-FLT (n = 5) or F-18-FDG (n = 5). Pretreatment of the animals with thymidine phosphorylase (>1,000 U/kg, intravenously) before injection of F-18-FLT proved to be necessary to reduce the serum levels of endogenous thymidine and achieve satisfactory tumor uptake of radioactivity. Results: Tumor-to-muscle ratios of F-18-FDG at 2 h after injection (13.2 +/- 3.0) were higher than those of F-18-FLT (3.8 +/- 1.3). F-18-FDG showed high physiologic uptake in brain and heart, whereas F-18-FLT was avidly taken up by bone marrow. F-18-FDG accumulated in the inflamed muscle, with 4.8 +/- 1.2 times higher uptake in the affected thigh than in the contralateral healthy thigh, in contrast to F-18-FLT, for which this ratio was not significantly different from unity (1.3 +/- 0.4). Conclusion; In F-18-FDG PET images, both tumor and inflammation were visible, but F-18-FLT PET showed only the tumor. Thus, the hypothesis that F-18-FLT has a higher tumor specificity was confirmed in our animal model.

We evaluated the suitability of fluorocarazolol for in vivo studies of cerebral beta-adrenoceptors because (S)-1'-[F-18]fluorocarazolol has a higher affinity to beta-adrenoceptors than to serotonergic receptors (pK(i) beta(1) 9.4, beta(2) 10.0, 5HT(1A) 7.4, 5HT(1B) 8.1) and rapidly crosses the blood-brain barrier. Methods: The (S)-[F-18]fluorocarazolol (74 MBq, >37 TBq/mmol) was intravenously administered to healthy volunteers on two separate occasions with an interval of at least 1 wk, The initial injection was without pretreatment, but before the second injection, the volunteers received the beta blocker (+/-)-pindolol (3 x 5 mg orally, during 18 hr). The brain was studied with a PET camera in dynamic mode. Results: Uptake of radioactivity delineated gray matter and was particularly high in the posterior cingulate, precuneus and striatum, Low uptake occurred in the thalamus, whereas the lowest uptake was observed in the white matter of the corpus callosum. After pindolol pretreatment, uptake was reduced and its distribution became homogeneous throughout the brain, The ratio of total-to-nonspecific binding was about 2 at 60 min, increasing to 2.5-2.75 at longer intervals. Conclusion: Fluorocarazolol is the first radioligand that can visualize cerebral beta-adrenoceptors and may enable monitoring of these binding sites during disease.

The characterization of pulmonary muscarinic receptors with PET is still in its infancy. Because approximately 70% of the lungs consists of air and pulmonary muscarinic receptor densities are low, ligands with high receptor affinity are required to obtain reasonable signal-to-noise ratios on PET images. Therefore, the potent C-11-labeled muscarinic antagonist N-methyl-piperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate methiodide ([R]-VC-002) was developed. We administered this radioligand to four healthy human volunteers to examine its suitability for studying pulmonary muscarinic receptors in vivo. Methods: [C-11]VC-002 (185 MBq, specific activity > 7.4 TBq/mmol) was intravenously injected on 2 separate days, with an interval of at least 1 wk. On the first day the volunteers were not pretreated, but on the second day they received the anticholinergic glycopyrronium bromide (Robinul; 2 x 0.1 mg intravenous) 25 and 30 min before the injection of the radiopharmaceutical. C[O-15]O scans (approximately 740 MBq [20 mCi] by inhalation) were acquired before the receptor scan to calculate pulmonary blood volume. Results: On PET images of the thorax, the lungs were clearly visible. After the volunteer was pretreated with glycopyrronium bromide, pulmonary uptake of the radioligand was reduced to 32% +/- 12% of the control value at 60 min postinjection and the lungs could no longer be seen. (R)-[C-11]-VC-002 was rapidly cleared from plasma and was slowly metabolized during the time course (60 min) of the PET scan. The fraction of radioligand representing parent compound decreased from 99.9% at the time of injection to 82% at 40-60 min postinjection, both in the presence and absence of Robinul. Pulmonary tissue-to-plasma ratios, calculated on a count-per-minute-per-gram basis, reached a plateau value of 17.8 +/- 1.2 at 40-50 min postinjection. Conclusion: [C-11]VC-002 appears to be suitable for in vivo studies of pulmonary cholinoceptors.