radiochemical yield
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Dopaminergic transporter (DAT) imaging with single photon emission computed tomography (SPECT) is used to diagnose Parkinson’s disease and to differentiate it from other neurodegenerative disorders without presynaptic dopaminergic dysfunction. The radioiodinated tropane alkaloids [123I]FP-CIT and [123I]β-CIT enable the evaluation of the integrity of DATs. Commonly, the labeling of these compounds is performed by electrophilic substitution of the alkylstannylated precursors with radioactive iodine and following purification by HPLC or solid phase extraction (SPE). This work presents the first radioiodination of β-CIT and FP-CIT with no carrier added [131I]NaI on a Scintomics GRP synthesis module. Free iodine-131 and impurities were removed by SPE over a C-18 Sep-Pak cartridge. We achieved a radiochemical yield of >75% and a radiochemical purity of >98% with both compounds. Our development of an automated synthesis on a commercially available synthesizer ensures robust and efficient labeling of [131I]FP-CIT and [131I]β-CIT starting with low concentrated radioiodine.

AbstractClinical production of 89Zr-radiolabeled antibodies (89Zr-mAbs) for positron emission tomography imaging relies on the pre-conjugation of desferrioxamine B (DFO) to the purified protein, followed by isolation and characterization of the functionalized intermediate, and then manual radiosynthesis. Although highly successful, this route exposes radiochemists to a potentially large radiation dose and entails several technological and economic hurdles that limit access of 89Zr-mAbs to just a specialist few Nuclear Medicine facilities worldwide. Here, we introduce a fully automated synthesis box that can produce individual doses of 89Zr-mAbs formulated in sterile solution in < 25 min starting from [89Zr(C2O4)4]4– (89Zr-oxalate), our good laboratory practice-compliant photoactivatable desferrioxamine-based chelate (DFO-PEG3-ArN3), and clinical-grade antibodies without the need for pre-purification of protein. The automated steps include neutralization of the 89Zr-oxalate stock, chelate radiolabeling, and light-induced protein conjugation, followed by 89Zr-mAb purification, formulation, and sterile filtration. As proof-of-principle, 89ZrDFO-PEG3-azepin-trastuzumab was synthesized directly from Herceptin in < 25 min with an overall decay-corrected radiochemical yield of 20.1 ± 2.4% (n = 3), a radiochemical purity > 99%, and chemical purity > 99%. The synthesis unit can also produce 89Zr-mAbs via the conventional radiolabeling routes from pre-functionalized DFO-mAbs that are currently used in the clinic. This automated method will improve access to state-of-the-art 89Zr-mAbs at the many Nuclear Medicine and research institutions that require automated devices for radiotracer production.

Background: Chitosan is a cationic biopolymer obtained from deacetylating chitin, a naturally compoundpresent in crustacean shell, fungi and exoskeleton of insects. Chitosan has various applications including drug and gene delivery systems, wound dressing and as scaffolds for tissue engineering, agriculture, textile, food and feed nanotechnology, waste water treatments. chitosan-TPP particle figure out as the most important and stable nanoparticle for chitosan application in various fields. Objective: At this study chitosan was chemically modified by sodium tripolyphosphate (TPP). Afterward, TPP-chitosan was radiolabeled with gallium-67 radionuclide. The effect of several factors on labeling yield such as chitosan solubility, acidity and concentration of TPP-chitosansolution, incubation time with gallium-67 were investigated. Methods: To prepare [67Ga] gallium-chitosan complex, chitosan (0.5 ml) was dissolved in 2.2 mCi of [67Ga] gallium chloride solution. The obtained solution was stirred for 5 min and then was kept for 30 min at room temperature. Radiochemical purity and radiolabeling yield was measured via radiochromatography that it was performed by using a radio thin-layer chromatography (TLC) scanner instrument. To investigate the effect of chitosan kind and concentration on the labeling yield, two kinds of chitosan (acid-soluble chitosan and water-soluble chitosan) with two different concentrations (1% and 0.5%) at different pH were used. In addition, labeling efficiency and stability of the 67Ga-TPP-chitosan complex (acidic/water soluble chitosan) at both concentrations (0.5 and 1%) at room temperature was assessed for 30, 45 and 60 min. Results: The incubation time has not significant effect on labeling yield. The acidic soluble chitosan, which has highest radiolabeling yield at pH=9.3-10.4, water soluble chitosan showed the highest radiolabeling yields at pH > 5. Also, the prepared complex was stable in the final solution at room temperature and can even be used 24 hours after preparation for further application. Conclusion: Taken together, the TPP modified water soluble chitosan at concentration 0.5 % depicted the highest radiochemical yield (>95 %) at the optimized condition (pH= 6.2–7.6). Therefore, TPP modified water soluble chitosan can be an effective carrier for therapeutic radionuclides for tumor treatment.

AbstractMany cancers of neuroendocrine origin overexpress cholecystokinin-2 receptors (CCK-2R) including medullary thyroid cancer, small cell lung cancer and other lung carcinoids. Fluorine-18 labelled peptides targeting CCK-2R enable direct visualization and quantification of this receptor in vivo using positron emission tomography imaging. CP04 1 and MG11 2 are two previously described truncated peptides derived from the native CCK-2R hormone ligand, gastrin. The N-terminus of the MG11 2 octopeptide was chemically modified with various fluorine containing aromatic (4-fluorobenzoate), heterocyclic (6-fluoronicotinate) and aliphatic (2-fluoropropionate) moieties. To assess the impact these modifications had on CCK-2R binding, ligand-binding assays were conducted using A431 cells overexpressing human CCK-2R. MG11 2 modified by 4-fluorobenzoate (FB-MG11 3) demonstrated the highest binding affinity (0.20 nM) followed by MG11 2 modified by 6-fluoronicotinate (FNic-MG11 4; 0.74 nM) and 2-fluoropropionate (FP-MG11 5; 1.80 nM), respectively. Whilst indirect labelling of MG11 2 using fluorine-18 labelled activated esters of fluorobenzoate and 6-fluoronicotinate was unsuccessful, direct fluorine-18 labelling at the N-terminus modified with 6-nitronicotinate afforded a 47.6% radiochemical yield of [18F]FNic-MG11. Unfortunately, [18F]FNic-MG11 4 was chemically unstable, decomposing slowly through defluorination, thereby impeding any further work with this radiotracer.

Abstract Angiotensin-converting enzyme 2 (ACE2), a transmembrane protein, is the main entry point for certain coronaviruses including the new coronavirus SARS-CoV-2 to enter cells. Synthesizing the PET imaging probe Al18F-DX600-BCH which is high-affinity ACE2 is aim to detect the expression of ACE2 in body and monitor the therapeutic effect. The Al18F-DX600-BCH was obtained manually with a 20.4% ± 5.2% radiochemical yield without attenuation correction and an over 99% purified radiochemical purity, being stable in vitro within 4 hours and cleared rapidly in blood (the half-lives of the distribution phase and clearance phase were 2.12 min and 25.31 min, respectively). Results of both biodistribution and PET imaging showed that Al18F-DX600-BCH was highly accumulated in the kidney (SUVkidney/normal > 50), and specific uptake in testis (SUVtestis/normal > 10) was observed in rat images. The kidney (++), gastrointestinal (++) and bronchial (+++) cells were evidenced of ACE2 positive by IHC staining of rats. A total of 10 volunteers were enrolled and received PET/CT 1 hour and 2 hours after injection or dynamic PET/CT during 0-330 seconds (NCT04542863), from which strong radioactivity accumulation was mostly observed in the genitourinary system (SUVrenal cortex = 32.00, SUVtestis = 4.56), and moderate accumulation in conjunctiva and nasal mucosa for several cases. This work firstly reported the probe Al18F-DX600-BCH targeting ACE2, conducting preliminary preclinical experiments and a total of 10 clinical transformations, which demonstrated the potential and possibility of non-invasive mapping of ACE2. Trial registration: ClinicalTrials.gov NCT04542863. Registered 9 September 2020.

The serotonin 5-HT2C receptor (5-HT2CR) is abundantly expressed throughout the central nervous system, and involved in a variety of neuroendocrine and neurobehavioral processes. The development of a selective radioligand that will enable in vivo imaging and quantification of 5-HT2CR densities represents a significant technological advancement in understanding both the normal function and pathophysiology of the 5-HT2CR. Four 7-halogen-2-phenyl isoindolones (7-F, Cl, Br, I) were synthesized and displayed high affinities for 5-HT2CR and high selectivity over 5-HT2A and 5-HT2B. [11C]7-Chloro-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (6) and [11C]7-iodo-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (9) were synthesized in high radiochemical yield of 37–44% [n = 10, decay corrected from end of (11C)CH3I synthesis] with high radiochemical purity via O-methylation with [11C]CH3I, respectively. MicroPET imaging studies in male rats with or without 5-HT2C antagonist SB-242084 showed that [11C]6 and [11C]9 display specific bindings to 5-HT2CR in the choroid plexus and hippocampus. In vivo microPET brain imaging studies in rhesus monkeys demonstrated that [11C]6 and [11C]9 exhibit excellent blood-brain barrier penetration. The contrast of bindings to the choroid plexus and hippocampus compared to the cerebellum peaked at 2.7 and 1.6, respectively, for [11C]6, and 3.7 and 2.7, respectively, for [11C]9, which were reduced by administration of a dose of SB-242084. Our results support the candidacy of [11C]6 and [11C]9 for further study as radioligands for in vivo quantitation of 5-HT2C sites by PET.

The integration of nuclear imaging analysis with nanomedicine has tremendously grown and represents a valid and powerful tool for the development and clinical translation of drug delivery systems. Among the various types of nanostructures used as drug carriers, nanovesicles represent intriguing platforms due to their capability to entrap both lipophilic and hydrophilic agents, and their well-known biocompatibility and biodegradability. In this respect, here we present the development of a labelling procedure of POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine)-based liposomes incorporating an ad hoc designed lipophilic NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) analogue, derivatized with an oleic acid residue, able to bind the positron emitter gallium-68(III). Based on POPC features, the optimal conditions for liposome labelling were studied with the aim of optimizing the Ga(III) incorporation and obtaining a significant radiochemical yield. The data presented in this work demonstrate the feasibility of the labelling procedure on POPC liposomes co-formulated with the ad hoc designed NOTA analogue. We thus provided a critical insight into the practical aspects of the development of vesicles for theranostic approaches, which in principle can be extended to other nanosystems exploiting a variety of bioconjugation protocols.

Abstract Background Prostate-specific membrane antigen is overexpressed in prostate cancer and it is considered a good target for positron emission tomography/computed tomography imaging of primary cancer and recurrent/metastatic disease, as well as for radioligand therapy. Different PSMA-analogues labeled with [68Ga]gallium have been investigated, showing excellent imaging properties; however, only small amounts can be produced for each radiolabeling. Recently, a [18F]fluoride labeled PSMA-inhibitor, [18F]PSMA-1007, has been introduced, and it has ensured large-scale productions, overcoming this limitation of [68Ga]PSMAs. In this study, PSMA-1007 has been labeled with low (A), medium (B) and high (C) starting activities of [18F]fluoride, in order to verify if radiochemical yield, radiochemical purity and stability of [18F]PSMA-1007 were affected. These parameters have been measured in sixty-five consecutive batches. In addition, the estimation of [18F]PSMA-1007 production costs is provided. Results The radiochemical yield for low and medium activities of [18F]fluoride was 52%, while for the high one it decreased to 40%. The radiochemical purity was 99% for all three activities. [18F]PSMA-1007 did not show radiolysis up to 8 h after the end of synthesis, confirming that the radiopharmaceutical is stable and suitable to perform diagnostic studies in humans for a long period of time after the end of radiolabeling. Furthermore, radiochemical stability was demonstrated in fetal bovine serum at 4 °C and 37 °C for 120′. Conclusions A starting activity of [18F]fluoride of 90 GBq (B) seems to be the best option enabling a final amount of about of 50 GBq of [18F]PSMA-1007, which is promising as it allows to: (a) perform a large number of scans, and/or (b) supply the radiopharmaceutical to any peripheral diagnostic centers in need.

Targeted α-therapy (TAT) can eradicate tumor metastases while limiting overall toxicity. One of the most promising α-particle emitters is astatine-211 (211At). However, 211At-carbon bonds are notoriously unstable in vivo and no chelators are available. This hampers its adoption in TAT. In this study, the stability of 211At on the surface of gold nanoparticles (AuNPs) was investigated. The employed AuNPs had sizes in the 25–50 nm range. Radiolabeling by non-specific surface-adsorption in >99% radiochemical yield was achieved by mixing 211At and AuNPs both before and after polyethylene glycol (PEG) coating. The resulting 211At-AuNPs were first challenged by harsh oxidation with sodium hypochlorite, removing roughly 50% of the attached 211At. Second, incubation in mouse serum followed by a customized stability test, showed a stability of >95% after 4 h in serum. This high stability was further confirmed in an in vivo study, with comparison to a control group of free 211At. The AuNP-associated 211At showed low uptake in stomach and thyroid, which are hallmark organs of uptake of free 211At, combined with long circulation and high liver and spleen uptake, consistent with nanoparticle biodistribution. These results support that gold surface-adsorbed 211At has high biological stability and is a potentially useful delivery system in TAT.