Current Radiopharmaceuticals - Volume 1, Issue 2, 2008

A selective and potent iNOS inhibitor, 8-fluoro-3-(4-fluorophenyl)-3,4-dihydro-1-isoquinolinamine (IC50 =0.16 μM) has been developed recently [8]. Based on that inhibitor, a novel PET imaging tracer intended for in vivo assessment of the iNOS, the F-18 labeled 8-fluoro-3-(4-[18F]fluorophenyl)-3,4-dihydro-1-isoquinolinamine ([18F]FFDI) was synthesized. [18F]FFDI was first prepared with radiochemical yield of 12-28% (with decay correction to EOS), low specific radioactivity, and low chemical purity by the direct aromatic nucleophilic substitution of 8-fluoro-3-(4-nitrophenyl)-3,4-dihydro-1-isoquinolinamine. Here an alternate two step synthesis is reported, in which nucleophilic [18F]fluoride substitution of 4-nitro-benzaldehyde and 4-N,N,N-trimethylammoniumbenzaldehyde triflate yielded 4-[18F]fluorobenzaldehyde, which was then converted to N-Trimethylsilyl-4-[18F]fluorobenzaldimine. N-Trimethylsilyl-4-[18F]fluorobenzaldimine reacted with the 2-fluoro-6-methyl-benzonitrile to form [18F]FFDI. The total synthesis took 115-128 min and the isolated yield was in the range of 15-26% (with decay correction to EOS), the radiochemical purity of the final product was higher than 99% and the specific radioactivity at the end of synthesis was typically 1212 ± 870 Ci/mmol (n=3). The final product was prepared as a sterile saline solution suitable for in vivo use on animals.

To illustrate the role of radiopharmaceuticals in characterizing non-hypersecreting adrenal masses, 56 patients with non-hypersecreting unilateral adrenal tumors detected on CT and/or MR underwent adrenal scintigraphy. A total of 83 radionuclide studies was acquired; in particular, 24 patients underwent nor-cholesterol scan, 23 patients had metaiodobenzylguanidine (MIBG) imaging, 26 patients had deoxyglucose (FDG) studies and 10 patients underwent somatostatin analogs (SAs) examinations. Histology (n=32) or biopsy (n=24) were obtained; lesions were 19 adenomas, 4 cysts, 1 myelolipoma, 1 neurinoma, 2 ganglioneuromas, 5 benign pheochromocytomas, 4 pseudotumors, 6 carcinomas, 2 sarcomas, 1 fibro-histiocytoma and 11 metastases. For nor-cholesterol, sensitivity, specificity and accuracy for detection of adenoma were 100%, 71% and 92%, respectively; positive predictive value (PPV) was 89%, while negative predictive value (NPV) was 100%. For MIBG, sensitivity, specificity and accuracy for detection of pheochromocytoma were 100%, 94% and 96%, respectively; PPV was 83%, while NPV was 100%. For FDG, sensitivity, specificity and accuracy for detection of malignancies were 100%, 100% and 100%, respectively; PPV and NPV were 100%; furthermore, in 7 patients with malignant adrenal tumors, FDG imaging scan was able to reveal extra-adrenal tumor sites (n=29). For SAs, sensitivity, specificity and accuracy for detection os Sas receptors were 80%, 100% and 90%, respectively; PPV was 100%, while NPV was 83%. In non-hypersecreting adrenal masses, nuclear imaging using specific labeled radiopharmaceuticals such as nor-cholesterol, MIBG, FDG and SAs may provide functional information for tissue characterization. Nor-cholesterol and MIBG scans are able to identify benign tumors such as adenoma and pheochromocytoma respectively, while FDG and SAs imaging allow the recognition of malignant adrenal lesions. Thus, adrenal scintigraphy is recommended for tumor diagnosis in non-hypersecreting adrenal masses and, hence, for appropriate treatment planning of such patients, particularly when CT and/or MR findings are uncertain as well as inconclusive for lesion characterization.

A case of a patient with bronchioloalveolar cell predominate lung adenocarcinoma (BAC) studied using integrated Positron Emission Tomography and Computed Tomography (PET/CT) with both 18F-fluorodeoxyglucose ([18F]FDG-PET) and [11C]Choline ([11C]Choline-PET) is described, with the aim of evaluating a new non invasive imaging method to detect and stage BAC, and providing information on tumour biology in vivo. The information derived from combining the two tracers could help in distinguishing lung adenocarcinoma with large BAC components ([18F]FDG negative and [11C]Choline positive) from inflammatory lesion ([18F]FDG and [11C]Choline positive). In addition, the simultaneous use of two PET tracers, evaluating two different metabolic pathways, together with histopathologic, immunohistochemical and gene expression analysis, could help to improve understanding of tumour in vivo behaviour.

The intense focus of radiochemical damage and cytotoxicity induced by Auger electron emitters is well known and provides a basis for their potential use in cancer therapy. Auger electron-emitting radionuclides decay by electron capture and/or internal conversion. The key feature of these modes of decay is the simultaneous release of low energy electrons, collectively known as Auger electrons. The unique characteristic of the majority of these electrons is their ultra short-range - they traverse only molecular dimensions - in biological tissue, resulting in a highly localized energy deposition in the immediate site of the decaying radionuclide. Therefore, Auger emitters have the potential to provide exquisite cell specificity in targeted cancer radiotherapy applications. However, their very limited effective range implies that there is a requirement to deliver these radionuclides to the DNA of target cells, to realize their maximum potential in cancer therapy. The radiobiological properties and therapeutic potential of Auger emitters has been the subject of intense exploration by a small but dedicated group of researchers for the past four decades. In this article we focus on recent advances relating to targeted cancer therapy with Auger electron-emitting radionuclides. State-of-the-art technologies for potential DNA-targeted cancer radiotherapy with Auger emitters are also presented.

Diagnosing osteomyelitis is clinically challenging. Laboratory tests are of limited utility, and other than isolation of the offending organism, diagnostic imaging tests are of paramount importance. There are a myriad of scintigraphic tests from which to choose, and no single test is optimal for all indications. With an accuracy of more than 90%, bone scintigraphy is the radionuclide test of choice for diagnosing osteomyelitis in unviolated bone. The test is less useful in violated bone conditions. Gallium-67 citrate imaging has been used in conjunction with the bone scan to improve test specificity. The overall accuracy of bone/gallium imaging, which is usually reserved for spinal osteomyelitis, is about 65%-80%. Except in the spine, combined radiolabeled leukocyte-marrow imaging is the radionuclide procedure of choice for diagnosing complicated osteomyelitis. The accuracy of the test is about 80%-90%. The in-vitro labeling procedure is a significant drawback to the test, and despite numerous attempts, no satisfactory in vivo labeling method is available. Recent work indicates that FDG PET is useful in the diagnosis of osteomyelitis. This tracer has shown promise for detecting acute and chronic infection in the axial and peripheral skeleton and has been reported to be highly accurate in suspected implant- (except prosthetic joint) associated infections. Increased FDG uptake, however, also is associated with inflammatory arthritis, acute fractures, normally healing bone and degenerative changes. Much investigation is still needed to determine the precise role of this procedure in musculoskeletal infection. Radiolabeled antibiotics and antimicrobials, which should in theory be highly specific for infection, have been investigated but are not in routine clinical use. It is important to recognize that no single tracer is equally efficacious in all regions of the skeleton and the selection of the appropriate study should be governed by the clinical question posed.

For radionuclide therapy of hepatocellular carcinoma, there have been many attempts to label Lipiodol (an iodinated ester of popyseed oil) with therapeutic radioisotopes, including 131I, 90Y, 186Re and 188Re. 131I-labelled Lipiodol is a commercially available radiopharmaceutical that is currently used in many countries. Nonetheless, despite encouraging results, there are some disadvantages with Iodine- 131, in particular the low-energy beta and high-energy gamma emissions as well as its long half-life. Rhenium-188 is an attractive alternative, since it has a higher beta energy coupled with a shorter physical half-life. In addition, 188Re emits a 155 keV γ-ray with an abundance of 15 % suitable for monitoring biodistribution and calculating dosimetry. A further advantage is that 188Re is now conveniently produced via a 188W/188Re generator system, enabling the on-site production of 188Re-radiopharmaceuticals. Over the last few years, efforts to label Lipiodol with 188Re have led to a very active area of research. Two strategies have been studied, namely i) covalent bonding between Lipiodol and the 188Re-chelate, and ii) solubilisation of a lipophilic 188Re-complex into cold Lipiodol. While some of these approaches are currently under clinical investigation, one of them is being sponsored by the International Atomic Energy Agency. The preliminary results indicate the feasibility of using rhenium-188, which shows good tolerance and good response rates in the treatment of unresectable HCC as well as in adjuvant or neo-adjuvant settings.

There is strong interest in clinical research to be able to study cannabinoid subtype-1 (CB1) receptors in living human brain with positron emission tomography (PET). Here, we aimed to prepare and compare in monkey three structurally-related high potency candidate PET radioligands for CB1 receptors based on the 1,5-diarylpyrazole platform, namely [O-methyl-11C][N-(piperidin-1-yl)-5-(4- methoxyphenyl)-1-(2-bromophenyl)-4-methyl-1H-pyrazole-3-carboxamide] ([11C]4), its 2-chloro analog ([11C]NIDA 41087, [11C]3), and its 4-cyano analog ([11C]JHU75575, [11C]5). Each radioligand was prepared by treatment of its O-desmethyl precursor with [11C]iodomethane and purified by HPLC. After intravenous injection of [11C]3, [11C]4 or [11C]5 into rhesus monkey, PET showed that brain uptake of radioactivity distributed according to the rank order of known CB1 receptor densities. Thereafter, radioactivity in all regions increased for [11C]3 and [11C]4, but declined for [11C]5, to the end of scanning (120 min after injection). Under conditions in which CB1 receptors were pre-blocked with a selective inverse agonist, initial brain uptakes of radioactivity for each radioligand were higher than under baseline conditions and for [11C]3 and [11C]4 were followed by rapid decreases to a plateau level whereas [11C]5 declined continuously. Radio-HPLC of plasma showed that each radioligand was rapidly metabolized. Although [11C]3 and [11C]4 gave some CB1 receptor- specific signals in monkey brain, these are probably contaminated with brain-penetrating radiometabolite(s). In contrast, [11C]5 gives an appreciable CB1 receptor-specific signal with a fast washout of non-specific binding.

A convenient remotely-controlled synthesis of no-carrier-added sodium [18F]fluoroacetate is described. Three ethyl esters 1a- 1c and three t-butyl esters 3a-3c containing either a methanesulfonyloxy- (OMs), p-toluenesulfonyloxy- (OTs) or p-nitrobenzenesulfonyloxy (ONs) leaving group were investigated as labeling precursors. The optimized radiosynthesis of n.c.a. sodium [18F]fluoroacetate was performed in two steps: (1) Incorporation of fluorine into (methanesulfonyloxy)-acetic acid t-butyl ester 3a as the superior labeling precursor in CH3CN at 100 ° C for 5 min followed by (2) acidic hydrolysis of the resulting [18F]fluoroacetic acid t-butyl ester at 100 ° C for 10 min to afford [18F]fluoroacetic acid. Several consecutive purification steps using anion exchange cartridges (Alltech Maxi-Clean SAX) and Sep-Pak neutral alumina cartridges gave sodium [18F]fluoroacetate in reproducible radiochemical yields of 20-25% (decay-corrected, n=20) in high radiochemical purity (>99%) within 50 min. Radiopharmacological characterization of sodium [18F]fluoroacetate was studied in Wistar rats and HT-29 tumor-bearing mice in comparison with [11C]acetate.

The aim of this work was to develop a PET radiotracer which would enable the study of central serotonin 5-HT4 receptors in man using positron emission tomography (PET). A procedure was developed for labelling SB207145, a potent and selective 5-HT4 antagonist, with the short-lived positron emitting radionuclide 11C. Alkylation of the corresponding desmethyl compound with 11C-methyl iodide afforded [11C]SB207145 in 50 - 60 %radiochemical yield (decay corrected to end of cyclotron bombardment), specific activities of > 50 GBq/μmole and radiochemical purities greater than 95%. PET studies in pig showed [11C]SB207145 rapidly entered the brain reaching peak concentrations at 10 - 20 mins post administration, followed by washout from tissue. In humans the tissue kinetics of the tracer was slower, reaching peak tissue concentrations at 30 - 60 mins post administration. In both species, the observed rank order of regional brain concentrations was striatum > thalamus > cortical regions > cerebellum, consistent with the known distribution and concentration of 5-HT4 receptors from in vitro studies. In pig, on administration of 0.5 mg/kg SB207040, a selective 5-HT4 antagonist, the specific binding of [11C]SB207145 was reduced to level of the cortex, demonstrating saturability of the 5-HT4 receptor population. In conclusion, a new PET radioligand is described which enables the study of 5-HT4 receptors in vivo in humans for the first time using PET.

Introduction: Neuroendocrine cells of the prostate are regulatory cells containing biogenic amines and certain neuropeptides such as chromogranin A (CgA). In the present study we evaluated the usefulness of serum CgA for monitoring prostate cancer progression. CgA levels were correlated to serum Prostate Specific Antigen (PSA) levels, bone scan findings and Gleason score. Methods: In this study we evaluated 122 patients with prostate cancer (PCa) diagnosed with prostate biopsy and 40 blood donors serving as the control group (CG). In both groups we measured serum CgA and PSA values. All PCa patients had locally advanced or metastatic disease and received complete androgen blockade. In the PCa group bone scanning with 925 MBq 99mTc-MDP revealed the presence of bone metastatic lesions in 53 patients (32 with more than three hot spots and 21 with less than three hot spots), while the remaining 69 patients had no bone metastases. At one-year follow-up we re-evaluated serum CgA, PSA and bone scans in both groups. Results: The serum levels of CgA and PSA were significantly higher in patients with PCa and bone metastases compared to patients with PCa without bone metastases (p<0.001). Elevated serum levels of CgA, higher than those of PSA, were found in patients with multiple bone metastases and Gleason score >7. Sensitivity and specificity values were 65% and 90% respectively for CgA alone (at 70nmol/L). The sensitivity and specificity of both studies combined (CgA and PSA) were increased to 88% and 97% respectively. Conclusions: Serum CgA is emerging as a potentially valuable marker for predicting the presence of bone metastases in patients with PCa. CgA combined with PSA improves the accuracy for predicting progression of the disease for patients with advanced PCa.

1-Amino-2-[3-13C]propanol hydrochloride (1) was synthesized by the coupling reaction of 2-phthalimidoacetyl chloride (2) with [13C]methylmagnesium iodide in the presence of copper iodide, followed by reduction with sodium borohydride and hydrolysis, in 64 % total yield from the 13C-source. All 13C- and 15N-isotopomers of 1-amino-2-propanol are now obtainable by using appropriate combinations of 13C-labeled sodium acetate, 13C- and/or 15N-labeled glycine, and potassium [15N]phthalimide.

Synthesis of L-[3-13C]tryptophan (2) from N,N-dimethyl[13C]formamide (4) and Dellaria's oxazinone 1 as a chiral glycine equivalent was achieved. Vilsmeier reaction of indole (5) and N,N-dimethyl[13C]formamide (4) afforded a good yield of indole-3-[13C]carbaldehyde (3), which was converted to the bromide 8. Diastereoselective alkylation of the enolate of 1 with the bromide 8 proceeded with high diastereoselectivity to give 9. Ethanolysis, hydrogenolysis and hydrolysis of 9 gave L-[3-13C]tryptophan (2).