Design, synthesis, and evaluation of positron emission tomography/fluorescence dual imaging probes for targeting facilitated glucose transporter 1 (GLUT1).

Increased energy metabolism followed by enhanced glucose consumption is a hallmark of cancer. Most cancer cells show overexpression of facilitated hexose transporter GLUT1, including breast cancer. GLUT1 is the main transporter for 2-deoxy-2-[18F]fluoro-d-glucose (2-[18F]FDG), the gold standard of positron emission tomography (PET) imaging in oncology. The present study's goal was to develop novel glucose-based dual imaging probes for their use in tandem PET and fluorescence (Fl) imaging. A glucosamine scaffold tagged with a fluorophore and an 18F-label should confer selectivity to GLUT1. Out of five different compounds, 2-deoxy-2-((7-sulfonylfluoro-2,1,3-benzoxadiazol-4-yl)amino)-d-glucose (2-FBDG) possessed favorable fluorescent properties and a similar potency as 2-deoxy-2-((7-nitro-2,1,3-benzoxadiazol-4-yl)amino)-d-glucose (2-NBDG) in competing for GLUT1 transport against 2-[18F]FDG in breast cancer cells. Radiolabeling with 18F was achieved through the synthesis of prosthetic group 7-fluoro-2,1,3-benzoxadiazole-4-sulfonyl [18F]fluoride ([18F]FBDF) followed by the reaction with glucosamine. The radiotracer was finally analyzed in vivo in a breast cancer xenograft model and compared to 2-[18F]FDG. Despite favourable in vitro fluorescence imaging properties, 2-[18F]FBDG was found to lack metabolic stability in vivo, resulting in radiodefluorination. Glucose-based 2-[18F]FBDG represents a novel dual-probe for GLUT1 imaging using FI and PET with the potential for further structural optimization for improved metabolic stability in vivo.

THE STRUCTURE OF Hp(0.07) VALUES OBTAINED BY THE NUCLEAR MEDICINE PERSONNEL DURING 18F-FDG PRODUCTION AND INJECTION.

The production of 18F-FDG is a multi-stage process, which includes not only obtaining the marker and labelling the radiopharmaceutical but also carrying out the quality control of the obtained compound. The staff can be exposed to ionizing radiation at any stage of production. This article presents the results of hands exposure of staff members employed in a facility, where 18F-FDG is produced and injected into patients. High-sensitivity thermoluminescent detectors (MCP-N) were used for measurements. The measurements were conducted with regard to the occupational structure the employees and the performed procedures. The obtained results showed that the highest risk of radiation exposure for personnel was associated with the quality control of the radiopharmaceutical. The daily doses registered by MCP-N detectors on fingertips reached 4.5 mSv, which may result in exceeding the annual radiation limit of 500 mSv.

Synthesis and evaluation of an N-[18F]fluorodeoxyglycosyl amino acid for PET imaging of tumor metabolism.

INTRODUCTION: The limitations of [18F]fluorodeoxyglucose ([18F]FDG), including producing false-positive or -negative results, low image contrast in brain tumor diagnosis and poor differentiation of tumor and inflammatory, necessitate the development of new radiopharmaceuticals. In the present study, a novel [18F]fluoroglycoconjugate tracer, [18F]FDGly-NH-Phe, for tumor metabolism imaging was prepared and evaluated. METHODS: [18F]FDGly-NH-Phe was prepared by condensing [18F]FDG with L-4-aminophenylalanine in an acidic condition, and purified with semi-preparative-high performance liquid chromatography (HPLC). The in vitro stability study was conducted in phosphate-buffered saline (PBS, pH 4.0-9.18) at room temperature (RT) and in fetal bovine serum (FBS) at 37 °C. The preliminary cellular uptake studies were performed using Hep-2 cell. The bio-distribution studies, PET/CT imaging and metabolism studies were performed and compared with [18F]FDG on ICR or BALB/c nude model mice. RESULTS: [18F]FDGly-NH-Phe was derived from a direct condensation of [18F]FDG with L-4-aminophenylalanine with high stability in FBS and PBS (pH of 6.5-9.18). In vitro cell experiments showed that [18F]FDGly-NH-Phe uptake in Hep-2 cells was primarily transported through amino acid transporters including Na+-dependent A system, ASC system, and system B0,+ system. The bio-distribution of [18F]FDGly-NH-Phe in normal ICR mice showed faster blood radioactivity clearance, and lower uptake in brain and heart than [18F]FDG. The performance of PET/CT imaging for [18F]FDGly-NH-Phe in the mice model manifested excellent tumor visualization, high tumor-to-background ratios, and low accumulation in inflammatory lesions. Metabolism studies for [18F]FDGly-NH-Phe indicated high in vivo stability in plasma and urine and decomposition into [18F]FDG in the tumor microenvironment. CONCLUSION: The results demonstrated that [18F]FDGly-NH-Phe as a novel amino acid PET tracer showed the capability to differentiate tumor from inflammation, and the potentials for future clinical applications.

THYROID EXPOSURE DURING 18F-FDG PRODUCTION PROCEDURES.

The production of radiopharmaceuticals for the needs of positron emission tomography (PET), in particular 18F-FDG, is a multi-step process performed most often by physicists and chemists. The monitoring of occupational exposure of staff employed in radiopharmaceutical production centres includes the measurement of the Hp(10) and Hp(0.07) values. Occupational exposure to ionising radiation means that the thyroid may be, among others, affected by the radiation field. This work analyses the exposure of the thyroid gland of employees of centres that produce the isotopes for PET, in particular fluorine-18. The analysis take into account the employment structure and work system of the discussed centres. Measurements were carried out by using high-sensitivity thermoluminescence detectors (MCP-N). The measurements covered 17 employees. Our results show that the estimated maximum annual thyroid gland exposure will not exceed 30 mSv.

The effect of work system on the hand exposure of workers in 18F-FDG production centres.

The production of the 18F isotope-the marker of deoxyglucose (18F-FDG)-the radiopharmaceutical most commonly used in the oncological diagnostic technique of positron emission tomography, requires a cyclotron device. At present, there are nine facilities working in Poland that are equipped with cyclotrons used for producing the short-lived isotopes. The aim of the paper is to determine the hand exposure of workers employed in the two 18F-FDG production centres taking in to account the production procedures and work system in those facilities. Measurements, which included all professional workers exposed to ionizing radiation that were employed in two facilities, were performed by using high-sensitivity thermoluminescent detectors during the routine activities of the personnel. The work system used at the production centre has an impact on the level of the recorded doses. Among the production procedures performed by the staff, the highest ionizing radiation doses have been received by the staff during the 18F-FDG quality control. The maximum estimated annual Hp(0.07) for chemists from the quality control department can exceed the annual skin limit dose (500 mSv). The source of lowest doses on the hands are the cyclotron operating procedure and the 18F-FDG production, provided that these procedures can't be combined with other production procedures.

Development of a disposable kit with fully automatic self-shielding reactor for [18F]FDG synthesis.

A self-shielding device for the synthesis of radiopharmaceuticals was developed and fabricated in this study. Radiation exposure was minimized by the self-shielding of the kit, installation of the disposable kit in the auxiliary chamber while in a shielded state, and discharge of the kit into a radioactive waste container upon completion of the synthesis process. The developed self-shielding synthesis kit was tested by synthesizing 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) in order to verify its performance.

Linker structure-activity relationships in fluorodeoxyglucose chlorambucil conjugates for tumor-targeted chemotherapy.

Nitrogen mustards, such as chlorambucil (CLB), can cause adverse side-effects due to ubiquitous distribution in non-target organs. To minimize this toxicity, strategies of tumor-targeting drug delivery have been developed, where a cytotoxic warhead is linked to a tumor-cell-specific small ligand. Malignant cells exhibit marked glucose avidity and an accelerated metabolism by aerobic glycolysis, known as the Warburg effect, and recognized as a hallmark of cancer. A targeting approach exploiting the Warburg effect by conjugation of CLB to 2-fluoro-2-deoxyglucose (FDG) was previously reported and identified two peracetylated glucoconjugates 2 and 3 with promising antitumor activities in vivo. These results prompted us to investigate the importance of the spacer in this tumor-targeting glucose-based conjugates. Here we report the chemical synthesis and an in vitro cytotoxicity evaluation, using a 5-member panel of human tumor cell lines and human fibroblasts, of 16 new CLB glucoconjugates in which the alkylating drug is attached to the C-1 position of FDG via different linkages. We studied the structure-activity relationships in the linker, and evidenced the positive impact of an aromatic linker on in vitro cytotoxicity: compound 51 proved to be the most active FDG-CLB glucoside, characterized by a bis-aromatic spacer tethered to CLB through an amide function.

Automated synthesis of N-(2-[18 F]Fluoropropionyl)-l-glutamic acid as an amino acid tracer for tumor imaging on a modified [18 F]FDG synthesis module.

N-(2-[18 F]Fluoropropionyl)-l-glutamic acid ([18 F]FPGLU) is a potential amino acid tracer for tumor imaging with positron emission tomography. However, due to the complicated multistep synthesis, the routine production of [18 F]FPGLU presents many challenging laboratory requirements. To simplify the synthesis process of this interesting radiopharmaceutical, an efficient automated synthesis of [18 F]FPGLU was performed on a modified commercial fluorodeoxyglucose synthesizer via a 2-step on-column hydrolysis procedure, including 18 F-fluorination and on-column hydrolysis reaction. [18 F]FPGLU was synthesized in 12 ± 2% (n = 10, uncorrected) radiochemical yield based on [18 F]fluoride using the tosylated precursor 2. The radiochemical purity was ≥98%, and the overall synthesis time was 35 minutes. To further optimize the radiosynthesis conditions of [18 F]FPGLU, a brominated precursor 3 was also used for the preparation of [18 F]FPGLU, and the improved radiochemical yield was up to 20 ± 3% (n = 10, uncorrected) in 35 minutes. Moreover, all these results were achieved using the similar on-column hydrolysis procedure on the modified fluorodeoxyglucose synthesis module.

Efficient automated synthesis of 2-(5-[18F]fluoropentyl)-2-methylmalonic acid ([18F]ML-10) on a commercial available [18F]FDG synthesis module.

[18F]ML-10 (2-(5-[18F]fluoro-pentyl)-2-methylmalonic acid) is a small molecule positron emission tomography (PET) probe for apoptosis imaging. Automated synthesis of [18F]ML-10 was developed by using two different purification methods through a direct saponification procedure on a modified commercial [18F]Fluoro-2-Deoxyglucose ([18F]FDG) synthesizer. C18 purification method 1: The final [18F]ML-10 solution containing ethanol was obtained with radiochemical yields of 60±5% (n=5) at the end of bombardment (EOB) and radiochemical purity of 98% in 35min. Al2O3 and SCX purification method 2: To avoid possible side effects of a conventional ethanol-containing formulation, an new ethanol-free solution of [18F]ML-10 was also developed, the radiochemical yields was 50±5% (n=5, EOB) within 45min and the radiochemical purity was 98%.

Management of radioactive waste gases from PET radiopharmaceutical synthesis using cost effective capture systems integrated with a cyclotron safety system.

The emphasis on the reduction of gaseous radioactive effluent associated with PET radiochemistry laboratories has increased. Various radioactive gas capture strategies have been employed historically including expensive automated compression systems. We have implemented a new cost-effective strategy employing gas capture bags with electronic feedback that are integrated with the cyclotron safety system. Our strategy is suitable for multiple automated 18F radiosynthesis modules and individual automated 11C radiosynthesis modules. We describe novel gas capture systems that minimize the risk of human error and are routinely used in our facility.

A two-center study for the quality control of [(18)F]FDG using FASTlab phosphate cassettes.

OBJECTIVE: The GE FASTlab radiosynthesis module is routinely used for the production of [(18)F]FDG, utilizing the commercially available phosphate cassettes. Because of the observation of a white precipitate in the product vial before the product expiry time, we re-examined the quality of the produced [(18)F]FDG solution. METHODS: Phosphate buffered [(18)F]FDG solution was synthesized on the FASTlab and analyzed at both National Taiwan University Hospital (NTUH) of Taiwan and Royal Brisbane and Women's Hospital (RBWH) of Australia. In addition to the standard product quality control (QC), the concentration of aluminum (Al(3+)) as probable cause of the precipitations in the [(18)F]FDG solution was analyzed by inductively coupled plasma mass spectrometry (ICP-MS at RBWH) and inductively coupled plasma optical emission spectrometry (ICP-OES at NTUH), and using three semi-quantitative methods at NTUH, Advantec(®) Alumi Check Test Strip, Quantofix(®) Aluminum Test Strip and MColortest™ Aluminum Test kit. RESULTS: The precipitates were observed in the [(18)F]FDG solution within 24 (NTUH) and 6 (RBWH) hours after the end of synthesis in 38-100 % of the batches, dependent on the batch of the FASTlab cassettes. Addition of metal-free HCl(aq) to aliquots of [(18)F]FDG containing precipitate, followed by ICP-MS analysis revealed Al(3+) concentrations of 70-80 ppm. Al(3+) concentrations of 10-12 ppm were detected in [(18)F]FDG batches that did not show any precipitation. In contrast, less than 5 ppm of the residual Al(3+) was detected by semi-quantitative methods in all batches. CONCLUSION: The US (USP), British (BP), European (EP) and Japanese (JP) pharmacopeias demand that [(18)F]FDG for injection should be clear and particulate free within the given shelf-life/expiration time. To avoid Al-phosphate precipitation within the product expiry time, FASTlab citrate cassettes, rather than phosphate cassettes, should be used for [(18)F]FDG production. Although testing for Al(3+) is not listed in the [(18)F]FDG monographs of the USP, BP and EP, residual Al(3+) levels should be considered in the interests of patient safety.

(18)F-Fluorodeoxyglucamines: Reductive amination of hydrophilic (18)F-fluoro-2-deoxyglucose with lipophilic amines for the development of potential PET imaging agents.

Maillard reaction of (18)F-FDG with biological amines results in the formation of (18)F-fluorodeoxyglycosylamines ((18)F-FDGly) as pseudo-Amadori products. To increase in vivo stability, we report the reductive amination of FDGly to provide reduced fluorodeoxyglucamines (FDGlu). (18)F-Fluorodeoxyglucamines ((18)F-FDGlu), resulting from linking (18)F-FDG (hydrophilic) to lipophilic molecules containing amine group may be useful as positron emission tomography (PET) imaging agents. Two amine derivatives, 7-chloro-8-hydroxy-3-methyl-l-(3'-aminophenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine (SCH 38548 for dopamine D1 receptors) and BTA-0 (for Aß amyloid) were reacted with FDG under reductive amination conditions to yield stable products, FDGluSCH and FDGluBTA. FDGluSCH had high binding affinity to rat brain dopamine D1 receptors with a Ki of 19.5 nM while FDGluBTA had micromolar affinity for human frontal cortex Aß plaques. (18)F-FDGluSCH was prepared in low to modest radiochemical yields and preliminary results showed binding to the rat striatum in brain slices. In vivo stability of(18)F-FDGluSCH needs to be determined. Our results suggest that (18)F-FDG is a useful 'radioactive synthon' for PET radiotracer development. Its usefulness will have to be determined on the basis of the structure-activity relationship of the target molecule.

Design of CGMP production of 18F- and 68Ga-radiopharmaceuticals.

OBJECTIVE: Radiopharmaceutical production process must adhere to current good manufacturing process (CGMP) compliance to ensure the quality of precursor, prodrug (active pharmaceutical ingredient, API), and the final drug product that meet acceptance criteria. We aimed to develop an automated system for production of CGMP grade of PET radiopharmaceuticals. METHODS: The hardware and software of the automated synthesizer that fit in the hot cell under cGMP requirement were developed. Examples of production yield and purity for (68)Ga-DOTATATE and (18)F-FDG at CGMP facility were optimized. Analytical assays and acceptance criteria for cGMP grade of (68)Ga-DOTATATE and (18)F-FDG were established. RESULTS: CGMP facility for the production of PET radiopharmaceuticals has been established. Radio-TLC and HPLC analyses of (68)Ga-DOTATATE and (18)F-FDG showed that the radiochemical purity was 92% and 96%, respectively. The products were sterile and pyrogenic-free. CONCLUSION: CGMP compliance of radiopharmaceuticals has been reviewed. (68)Ga-DOTATATE and (18)F-FDG were synthesized with high radiochemical yield under CGMP process.

Synthesis and preclinical characterization of [18F]FPBZA: a novel PET probe for melanoma.

INTRODUCTION: Benzamide can specifically bind to melanoma cells. A 18F-labeled benzamide derivative, [18F]N-(2-diethylaminoethyl)-4-[2-(2-(2-fluoroethoxy) ethoxy)ethoxy]benzamide ([18F]FPBZA), was developed as a promising PET probe for primary and metastatic melanoma. METHODS: [18F]FPBZA was synthesized via a one-step radiofluorination in this study. The specific uptake of [18F]FPBZA was studied in B16F0 melanoma cells, A375 amelanotic melanoma cells, and NB-DNJ-pretreated B16F0 melanoma cells. The biological characterization of [18F]FPBZA was performed on mice bearing B16F0 melanoma, A375 amelanotic melanoma, or inflammation lesion. RESULTS: [18F]FPBZA can be prepared efficiently with a yield of 40-50%. The uptake of [18F]FPBZA by B16F0 melanoma cells was significantly higher than those by A375 tumor cells and NB-DNJ-pretreated B16F0 melanoma cells. B16F0 melanoma displayed prominent uptake of [18F]FPBZA at 2 h (7.81±0.82%ID/g), compared with A375 tumor and inflammation lesion (3.00±0.71 and 1.67±0.56%ID/g, resp.). [18F]FPBZA microPET scan clearly delineated B16F0 melanoma but not A375 tumor and inflammation lesion. In mice bearing pulmonary metastases, the lung radioactivity reached 4.77±0.36%ID/g at 2 h (versus 1.16±0.23%ID/g in normal mice). CONCLUSIONS: Our results suggested that [18F]FPBZA PET would provide a promising and specific approach for the detection of primary and metastatic melanoma lesions.

Fully automated production of diverse 18F-labeled PET tracers on the ELIXYS multireactor radiosynthesizer without hardware modification.

UNLABELLED: Fully automated radiosynthesizers are continuing to be developed to meet the growing need for the reliable production of PET tracers made under current good manufacturing practice guidelines. There is a current trend toward supporting kitlike disposable cassettes that come preconfigured for particular tracers, thus eliminating the need for cleaning protocols between syntheses and enabling quick transitions to synthesizing other tracers. Though ideal for production, these systems are often limited for the development of novel tracers because of pressure, temperature, and chemical compatibility considerations. This study demonstrated the versatile use of the ELIXYS fully automated radiosynthesizer to adapt and produce 8 different (18)F-labeled PET tracers of varying complexity. METHODS: Three-reactor syntheses of 2-deoxy-2-(18)F-fluoro-ß-d-arabinofuranosylcytosine (d-(18)F-FAC), 2-deoxy-2-(18)F-fluoro-5-methyl-ß-l-arabinofuranosyluracil (l-(18)F-FMAU), and 2-deoxy-2-(18)F-fluoro-5-ethyl-ß-d-arabinofuranosyluracil (d-(18)F-FEAU) along with the 1-reactor syntheses of d-(18)F-FEAU, (18)F-FDG, 3-deoxy-3-(18)F-fluoro-l-thymidine ((18)F-FLT), (18)F-fallypride, 9-(4-(18)F-fluoro-3-hydroxymethylbutyl)-guanine ((18)F-FHBG), and N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB), were all produced using ELIXYS without the need for any hardware modifications or reconfiguration. Synthesis protocols were adapted and slightly modified from those in the literature but were not fully optimized. Furthermore, (18)F-FLT, (18)F-FDG, and (18)F-fallypride were produced sequentially on the same day and used for preclinical imaging of A431 tumor-bearing severe combined immunodeficient mice and wild-type BALB/c mice. To assess future translation to the clinical setting, several batches of tracers were subjected to a full set of quality control tests. RESULTS: All tracers were produced with radiochemical yields comparable to those in the literature. (18)F-FLT, (18)F-FDG, and (18)F-fallypride were successfully used to image the mice, with results consistent with those reported in the literature. All tracers that were subjected to clinical quality control tests passed. CONCLUSION: The ELIXYS radiosynthesizer facilitates rapid tracer development and is capable of producing multiple (18)F-labeled PET tracers suitable for clinical applications using the same hardware setup.

Quantification of the activity of tritium produced during the routine synthesis of (18)F fluorodeoxyglucose for positron emission tomography.

Gamma emitting radioactive by-products generated during the cyclotron irradiation of (18)O labelled water by protons to produce (18)FDG (fluorodeoxyglucose) for positron emission tomography are well characterised. However, the production of tritium ((3)H) through the (18)O(p,t)(16)O nuclear reaction has not been investigated in detail. The aim of this study was to measure tritium activity produced during a large number of (18)FDG production runs in order to obtain a better perspective on its impact on radioactive waste management, particularly as regards storage and disposal. Tritium was assayed by liquid scintillation counting in recovered (18)O water from 24 separate production runs. The mean (SD) values of activity and activity concentration were 170 (20) kBq and 81 (8) kBq ml(-1) respectively. Both quantities were positively correlated with the activity of (18)F. Tritium was detected in much lower concentration in water used to rinse the target vessel. The activity of tritium is such that it is exempt from regulatory control and may be combined with bulk non-active waste for disposal as Very Low Level Waste. However, variations in the irradiation conditions or the procedures for the collection of recovered water might result in its classification as Low Level Waste, necessitating a more complex disposal regime.

Advances in processes for PET radiotracer synthesis: separation of [¹8F]fluoride from enriched [¹8O]water.

Positron emission tomography (PET) is a powerful scientific and clinical tool for the study and visualization of human physiology that can provide important information about metabolism and diseases such as cancer. At present, [(18)F]fluorodeoxyglucose ([(18)F]FDG) is the most frequently used radiotracer for the routine clinical evaluation of malignant tumors in a range of body tissues. FDG synthesis is continuously being developed to improve and simplify the synthetic procedure including the isolation of [(18)F]fluoride from [(18)O]water. There are many methods reported in literature for the isolation of [(18)F]fluoride, including evaporation, coat-capture-elution, the use of cation-exchange resin and electrode trapping. This review article gives an overview of some of the most common methods for the separation of [(18)F]fluoride ions from [(18)O]water, highlighting the potential strength of the methods and also problems and weaknesses for synthesis of (18)F PET tracers.

A "dose on demand" Biomarker Generator for automated production of [(18)F]F(-) and [(18)F]FDG.

The University of Oklahoma-College of Pharmacy has installed the first Biomarker Generator (BG75) comprising a self-shielded 7.5-MeV proton beam positive ion cyclotron and an aseptic automated chemistry production and quality control module for production of [(18)F]F(-) and clinical [(18)F]FDG. Performance, reliability, and safety of the system for the production of "dose on demand" were tested over several months. No-carrier-added [(18)F]F(-) was obtained through the (18)O(p,n)(18)F nuclear reaction by irradiation (20-40 min) of a >95% enriched [(18)O]H2O target (280 µl) with a 7.5-MeV proton beam (3.5-5.0 µA). Automated quality control tests were performed on each dose. The HPLC-based analytical methods were validated against USP methods of quality control. [(18)F]FDG produced by BG75 was tested in a mouse tumor model implanted with H441 human lung adenocarcinoma cells. After initial installment and optimization, the [(18)F]F(-) production has been consistent since March 2011 with a maximum production of 400 to 450 mCi in a day. The average yield is 0.61 mCi/min and 0.92 mCi/min at 3.8 µA and 5 µA, respectively. The current target window has held up for over 25 weeks against >400 bombardment cycles. [(18)F]FDG production has been consistent since June 2012 with an average of six doses/day in an automated synthesis mode (RCY≈50%). The release criteria included USP-specified limits for pH, residual solvents (acetonitrile/ethanol), kryptofix, radiochemical purity/identity, and filter integrity test. The entire automated operation generated minimal radiation exposure hazard to the operator and environment. As expected, [(18)F]FDG produced by BG75 was found to delineate tumor volume in a mouse model of xenograft tumor. In summary, production and quality control of "[(18)F]FDG dose on demand" have been accomplished in an automated and safe manner by the first Biomarker Generator. The implementation of a cGMP quality system is under way towards the ANDA submission and first clinical use of [(18)F]FDG produced by BG75.

18FDG synthesis and supply: a journey from existing centralized to future decentralized models.

Positron emission tomography (PET) as the functional component of current hybrid imaging (like PET/ CT or PET/MRI) seems to dominate the horizon of medical imaging in coming decades. 18Flourodeoxyglucose (18FDG) is the most commonly used probe in oncology and also in cardiology and neurology around the globe. However, the major capital cost and exorbitant running expenditure of low to medium energy cyclotrons (about 20 MeV) and radiochemistry units are the seminal reasons of low number of cyclotrons but mushroom growth pattern of PET scanners. This fact and longer half-life of 18F (110 minutes) have paved the path of a centralized model in which 18FDG is produced by commercial PET radiopharmacies and the finished product (multi-dose vial with tungsten shielding) is dispensed to customers having only PET scanners. This indeed reduced the cost but has limitations of dependence upon timely arrival of daily shipments as delay caused by any reason results in cancellation or rescheduling of the PET procedures. In recent years, industry and academia have taken a step forward by producing low energy, table top cyclotrons with compact and automated radiochemistry units (Lab- on-Chip). This decentralized strategy enables the users to produce on-demand doses of PET probe themselves at reasonably low cost using an automated and user-friendly technology. This technological development would indeed provide a real impetus to the availability of complete set up of PET based molecular imaging at an affordable cost to the developing countries.