Synthesis and evaluation of macrocyclic amino acid derivatives for tumor imaging by gallium-68 positron emission tomography

(68)Ga PET imaging in clinical oncology represents a notable development because the availability of (68)Ga is not dependent on a cyclotron. Furthermore, labeled amino acid derivatives have been proven to be useful for the imaging many tumor types. In the present study, we synthesized β-aminoalanine, γ-aminohomoalanine, and lysine conjugates of macrocyclic bifunctional chelating agents, such as, NOTA (1a-c) and DOTA (2a-c). The compounds produced were found to be potential useful as (68)Ga-PET imaging agents. In particular, they showed high tumor uptakes in vitro and in vivo, and had high labeling yields and excellent stabilities. The co-ordination chemistry of NOTA-monoamide compound 1a was studied by multinuclear NMR. In vitro studies showed that the synthesized compounds were taken up by cancer cells more than controls ((68)Ga-NOTA and (68)Ga-DOTA). Furthermore, in vivo studies showed that they have high tumor to muscle and tumor to blood ratios, and small-animal PET imaging revealed high tumor uptakes as compared with other organs, and high bladder activities, indicating rapid renal excretion. These results might motivate the use of (68)Ga amino acid PET for tumor diagnosis.     

Toward preparation of antibody-based imaging probe libraries for dual-modality positron emission tomography and fluorescence imaging

Two novel imaging agents trastuzumab-Cy5.5-CHX-A″ 1 and cetuximab-Cy7-CHX-A″ 2, bearing both a chelating moiety (CHX-A″) for sequestering metallic radionuclides (⁸⁶Y or ¹¹¹In) and the near infrared dye Cy5.5/Cy7, were prepared by a novel modular synthetic strategy as examples of dual-labeled, antibody-based imaging probe library. Fluorescent microscopy illustrated that 1 and 2 strongly bind to HER2-expressing cancer cells (e.g., NIH3T3–HER2⁺, SKOV-3) and to EGFR-expressing cancer cells (e.g., A431), respectively, thereby demonstrating that the functionality of the targeting moiety is conserved. Hence, the described novel synthesis strategy can be applied to engineer other tumor-targeted monoclonal antibody based probes for multimodality imaging.     

Approaches to the design of biochemical probes for positron emission tomography

Since the development of the 2-deoxy-D-glucose procedure by L. Sokoloff considerable advances have been made in the design of radiotracers for estimation of in-vivo biochemical parameters. Many of these advances are due to the development of positron emission tomography. As a result key biochemical processes can now be evaluated with newly developed positron-emitting labeled enzyme probes in man, in-vivo, allowing the study of a wide range of specific cellular processes in health and disease states.Special issue dedicated to Dr. Louis Sokoloff.     

Synthesis and evaluation of bifunctional tetrahydroxamate chelators for labeling antibodies with 89Zr for imaging with positron emission tomography

Two novel bifunctional tetrahydroxamate chelators 3 and 4 were synthesized and evaluated for labeling antibodies with ⁸⁹Zr for positron emission tomography imaging. Compared to previously reported tetrahydroxamate chelators 1 and 2 with an iminodiacetamide backbone, 3 and 4 were based on an extended iminodipropionamide and dipropylenetriamine backbone, respectively. Trastuzumab conjugates of 3 and 4 were efficiently labeled with ⁸⁹Zr (>95% radiochemical yield). The in vitro plasma stability of ⁸⁹Zr-4-Trastuzumab and especially ⁸⁹Zr-3-Trastuzumab was greatly improved over previously reported ⁸⁹Zr-1-Trastuzumab and ⁸⁹Zr-2-Trastuzumab, but their demetalation remained higher and faster than ⁸⁹Zr-deferoxamine (DFO)-Trastuzumab. These observations were confirmed by PET imaging and biodistribution in mice, with significant higher bone uptake for ⁸⁹Zr-4-Trastuzumab, followed by ⁸⁹Zr-3-Trastuzumab, and to a lesser extent for ⁸⁹Zr-DFO-Trastuzumab. Molecular modeling showed that 3 and 4 with an extended backbone could form eight-coordinate Zr-complexes as compared to only seven-coordinate Zr-complexes of 1 and 2. Our data suggest further elongation of linker length between hydroxamate motifs of this class of chelators is needed to reach a better Zr-coordination configuration and improve in vivo stability.     

In vivo evaluation of medical device-associated inflammation using a macrophage-specific positron emission tomography (PET) imaging probe

To image implant-surrounding activated macrophages, a macrophage-specific PET probe was prepared by conjugating folic acid (FA) and 2,2′,2″,2?-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetracetic acid (DOTA) to polyethylene glycol (PEG) and then labeling the conjugate with Ga-68. In vivo PET imaging evaluations demonstrate that the probe is able to detect foreign body reactions, and more importantly, quantify the degree of inflammatory responses to an implanted medical device. These results were further validated by histological analysis.     

Functional imaging of memory processes in humans: positron emission tomography and functional magnetic resonance imaging

Human memory is not a unitary function; it consists of multiple memory systems, with different characteristics and specialisations that are implemented in the brain. The cognitive neuroscience of human memory tries to comprehend how we encode, store, and retrieve memory items within and across those systems. The emergence of functional neuroimaging techniques offered the unprecedented opportunity to directly observe the brain regions engaged in memory functions. Brain imaging techniques can roughly be divided into those measuring the electric or magnetic fields generated by neuronal activity (EEG, magnetencephalography [MEG]) and those measuring the haemodynamic or metabolic sequelae of neuronal activity (positron emission tomography [PET], functional magnetic resonance imaging [fMRI]). Out of these techniques, the following two will be discussed in detail: fMRI and PET. Although functional neuroimaging is able to acquire images of the brain engaged in consolidating or retrieving memories, these processes are not clearly visible in the data. Statistical techniques are needed to reduce the complexity of the data and to extract the processes of interest. This article outlines the experimental and analytical procedures of neuroimaging studies with PET and fMRI. We will use a PET-study on episodic memory in human volunteers to illustrate design, analysis, and interpretation of functional imaging studies on memory.     

Strategies for the labeling of halogen-substituted peroxisome proliferator-activated receptor gamma ligands: potential positron emission tomography and single photon emission computed tomography imaging agents

Well-known as an important regulator of lipid metabolism and adipocyte differentiation, the peroxisome proliferator-activated receptor gamma (PPARgamma) also has potential use as a target for antitumor therapy in certain cancers. To develop agents for radionuclide imaging PPARgamma in vivo, we synthesized fluorine, bromine, and iodine-substituted analogs (1-3) of a high-affinity benzophenone-tyrosine PPARgamma ligand; all three analogs retain very high affinity for the PPARgamma receptor. In preparation for the synthesis of these PPARgamma ligands in radiolabeled form, we have synthesized two types of precursors: (a) an aryltributylstannane (9), from which the bromine and iodine-substituted analogs (2 and 3) can readily be prepared by electrophilic destannylation, and (b) three diaryliodonium tosylate derivatives (12a-c), precursors for nucleophilic aromatic fluorination using fluoride ion. Conditions were developed whereby the thiophenyliodonium tosylate (12c) underwent nucleophilic aromatic substitution with fluoride ion, efficiently and in short reaction times, to produce the desired fluorine-substituted target compound 1. These reactions laid the groundwork for producing these three PPARgamma ligands in radiolabeled form; in addition, our use of diaryliodonium ion precursors for aromatic fluorination in this series provides an example that should encourage application of this approach for radiofluorination of more complicated radiopharmaceuticals.     

Novel method to label solid lipid nanoparticles with 64cu for positron emission tomography imaging

Solid lipid nanoparticles (SLNs) are submicrometer (1-1000 nm) colloidal carriers developed in the past decade as an alternative system to traditional carriers (emulsions, liposomes, and polymeric nanoparticles) for intravenous applications. Because of their potential as drug carriers, there is much interest in understanding the in vivo biodistribution of SLNs following intravenous (i.v.) injection. Positron emission tomography (PET) is an attractive method for investigating biodistribution but requires a radiolabeled compound. In this work, we describe a method to radiolabel SLN for in vivo PET studies. A copper specific chelator, 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N',N',N'-tetraacetic acid (BAT), conjugated with a synthetic lipid, was incorporated into the SLN. Following incubation with (64)CuCl(2) for 1 h at 25 °C in 0.1 M NH(4)OAc buffer (pH 5.5), the SLNs (～150 nm) were successfully radiolabeled with (64)Cu (66.5% radiolabeling yield), exhibiting >95% radiolabeled particles following purification. The (64)Cu-SLNs were delivered intravenously to mice and imaged with PET at 0.5, 3, 20, and 48 h post injection. Gamma counting was utilized post imaging to confirm organ distributions. Tissue radioactivity (% injected dose/gram, %ID/g), obtained by quantitative analysis of the images, suggests that the (64)Cu-SLNs are circulating in the bloodstream after 3 h (blood half-life ～1.4 h), but are almost entirely cleared by 48 h. PET and gamma counting demonstrate that approximately 5-7%ID/g (64)Cu-SLNs remain in the liver at 48 h post injection. Stability assays confirm that copper remains associated with the SLN over the 48 h time period and that the biodistribution patterns observed are not from free, dissociated copper. Our results indicate that SLNs can be radiolabeled with (64)Cu, and their biodistribution can be quantitatively evaluated by in vivo PET imaging and ex vivo gamma counting.     

Performance and limitations of positron emission tomography (PET) scanners for imaging very low activity sources

Emerging applications for positron emission tomography (PET) may require the ability to image very low activity source distributions in the body. The performance of clinical PET scanners in the regime where activity in the field of view is <1 MBq has not previously been explored. In this study, we compared the counting rate performance of two clinical PET/CT scanners, the Siemens Biograph Reveal 16 scanner which is based on lutetium oxyorthosilicate (LSO) detectors and the GE Discovery-ST scanner which is based on bismuth germanate (BGO) detectors using a modified National Electrical Manufacturers Association (NEMA) NU 2-2007 protocol. Across the activity range studied (2–100 kBq/mL in a 5.5 mL line source in the NEMA scatter phantom), the BGO-based scanner significantly outperformed the LSO-based scanner. This was largely due to the effect of background counts emanating from naturally occurring but radioactive ¹⁷⁶Lu within the LSO detector material, which dominates the observed counting rate at the lowest activities. Increasing the lower energy threshold from 350 keV to 425 keV in an attempt to reduce this background did not significantly improve the measured NECR performance. The measured singles rate due to ¹⁷⁶Lu emissions within the scanner energy window was also found to be dependent on temperature, and to be affected by the operation of the CT component, making approaches to correct or compensate for the background more challenging. We conclude that for PET studies in a very low activity range, BGO-based scanners are likely to have better performance because of the lack of significant background.     

18F Labeled benzimidazole derivatives as potential radiotracer for positron emission tomography (PET) tumor imaging

This article reported the synthesis and bioevaluation of two [¹⁸F] labeled benzimidazole derivatives, 4-(5-(2-[¹⁸F] fluoro-4-nitrobenzamido)-1-methyl-1H-benzimidazol-2-yl) butanoic acid ([¹⁸F] FNBMBBA, [¹⁸F]a1) and 3-(2-fluoroethyl)-7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid ([¹⁸F] FEMPBBA, [¹⁸F]b1) for PET tumor imaging. The preparation [¹⁸F] FEMPBBA was completed in 1 h with overall radiochemical yield of 50–60% (without decay corrected). Biodistribution assay in S180 tumor bearing mice of both compounds were carried out, and the results are both meaningful. [¹⁸F] FEMPBBA which can be taken as a revision of [¹⁸F] FNBMBBA got an excellent result, and has significant advantages in some aspects compared with L-[¹⁸F] FET and [¹⁸F]-FDG in the same animal model, especially in tumor/brain uptake ratio. The tumor/brain uptake ratio of [¹⁸F] FEMPBBA gets to 4.81, 7.15, and 9.8 at 30 min, 60 min and 120 min, and is much higher than that of L-[¹⁸F] FET (2.54, 2.92 and 2.95) and [¹⁸F]-FDG (0.61, 1.02, 1.33) at the same time point. The tumor/muscle and tumor/blood uptake ratio of [¹⁸F] FEMPBBA is also higher than that of L-[¹⁸F] FET at 30 min and 60 min. This result indicates compound [¹⁸F] FEMPBBA is a promising radiotracer for PET tumor imaging.     

Development of radioligands with optimized imaging properties for quantification of nicotinic acetylcholine receptors by positron emission tomography

AimsThere is an urgent need for positron emission tomography (PET) imaging of the nicotinic acetylcholine receptors (nAChR) to study the role of the nicotinic system in Alzheimer's and Parkinson's diseases, schizophrenia, drug dependence and many other disorders. Greater understanding of the underlying mechanisms of the nicotinic system could direct the development of medications to treat these disorders. Central nAChRs also contribute to a variety of brain functions, including cognition, behavior and memory.Main methodsCurrently, only two radiotracers, (S)-3-(azetidin-2-ylmethoxy)-2-[¹⁸F]fluoropyridine (2-[¹⁸F]FA) and (S)-5-(azetidin-2-ylmethoxy)-2-[¹⁸F]fluoropyridine (6-[¹⁸F]FA), are available for studying nAChRs in human brain using PET. However, the “slow” brain kinetics of these radiotracers hamper mathematical modeling and reliable measurement of kinetic parameters since it takes 4–7 h of PET scanning for the tracers to reach steady state. The imaging drawbacks of the presently available nAChR radioligands have initiated the development of radioligands with faster brain kinetics by several research groups.Key findingsThis minireview attempts to survey the important achievements of several research groups in the discovery of PET nicotinic radioligands reached recently. Specifically, this article reviews papers published from 2006 through 2008 describing the development of fifteen new nAChR ¹¹C-and ¹⁸F-ligands that show improved imaging properties over 2-[¹⁸F]FA.SignificanceThe continuous efforts of radiomedicinal chemists led to the development of several interesting PET radioligands for imaging of nAChR including [¹⁸F]AZAN, a potentially superior alternative to 2-[¹⁸F]FA.     

Radiolabelled proteins for positron emission tomography: Pros and cons of labelling methods

Background

Dynamic biomedical research is currently yielding a wealth of information about disease-associated molecular alterations on cell surfaces and in the extracellular space. The ability to visualize and quantify these alterations in vivo could provide important diagnostic information and be used to guide individually-optimized therapy. Biotechnology can provide proteinaceous molecular probes with highly specific target recognitions. Suitably labelled, these may be used as tracers for radionuclide-based imaging of molecular disease signatures. If the labels are positron-emitting radionuclides, the superior resolution, sensitivity and quantification capability of positron emission tomography (PET) can be exploited.

Scope of review

This article discusses different approaches to labelling proteins with positron-emitting nuclides with suggestions made depending on the biological features of the tracers.

Major conclusions

Factors such as matching biological and physical half-lives, availability of the nuclide, labelling yields, and influences of labelling on targeting properties (affinity, charge and lipophilicity, cellular processing and retention of catabolites) should be considered when selecting a labelling strategy for each proteinaceous tracer.

General significance

The labelling strategy used can make all the difference between success and failure in a tracer application. This review emphasises chemical, biological and pharmacological considerations in labelling proteins with positron-emitting radionuclides.     

Development and evaluation of a 68Ga labeled pamoic acid derivative for in vivo visualization of necrosis using positron emission tomography

In this study, we labeled N,N′-bis(diethylenetriamine pentaacetic acid)-pamoic acid bis-hydrazide (bis-DTPA-PA) with the generator produced PET radionuclide gallium-68 and evaluated ⁶⁸Ga-bis-DTPA-PA as a potential tracer for in vivo visualization of necrosis by positron emission tomography (PET). Radiolabeling was achieved with a decay-corrected radiochemical yield of 63%. Biodistribution and in vivo stability studies in normal mice showed that ⁶⁸Ga-bis-DTPA-PA is cleared faster from normal tissue than the previously reported ^99mTc(CO)₃ complex with bis-DTPA-PA which on the other hand is more stable in vivo. ⁶⁸Ga-bis-DTPA-PA showed a 3.5–5 times higher binding to necrotic tissue than to viable tissue as shown by in vitro autoradiography while no statistically significant increased hepatic uptake was found in a biodistribution study in a mouse model of hepatic apoptosis. Specificity and avidity for necrosis was further evaluated in rats with a reperfused partial liver infarction and ethanol induced muscular necrosis. Dynamic microPET images showed a fast and prolonged uptake of ⁶⁸Ga-bis-DTPA-PA in necrotic tissue with in vivo and ex vivo images correlating well with histochemical stainings. With necrotic to viable tissue activity ratios of 8–15 on ex vivo autoradiography, depending on the necrosis model, ⁶⁸Ga-bis-DTPA-PA showed a faster and higher uptake in necrotic tissue than the ^99mTc(CO)₃ analog. These results show that ⁶⁸Ga-bis-DTPA-PA specifically binds to necrotic tissue and is a promising tracer for in vivo visualization of necrosis using PET.     

A novel method to label preformed liposomes with 64Cu for positron emission tomography (PET) imaging

Radiolabeling of liposomes with 64Cu (t(1/2)=12.7 h) is attractive for molecular imaging and monitoring drug delivery. A simple chelation procedure, performed at a low temperature and under mild conditions, is required to radiolabel preloaded liposomes without lipid hydrolysis or the release of the encapsulated contents. Here, we report a 64Cu postlabeling method for liposomes. A 64Cu-specific chelator, 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N',N',N'-tetraacetic acid (BAT), was conjugated with an artificial lipid to form a BAT-PEG-lipid. After incorporation of 0.5% (mol/mol) BAT-PEG-lipid during liposome formulation, liposomes were successfully labeled with 64Cu in 0.1 M NH4OAc pH 5 buffer at 35 degrees C for 30-40 min with an incorporation yield as high as 95%. After 48 h of incubation of 64Cu-liposomes in 50/50 serum/PBS solution, more than 88% of the 64Cu label was still associated with liposomes. After injection of liposomal 64Cu in a mouse model, 44+/-6.9, 21+/-2.7, 15+/-2.5, and 7.4+/-1.1 (n=4) % of the injected dose per cubic centimeter remained within the blood pool at 30 min, 18, 28, and 48 h, respectively. The biodistribution at 48 h after injection verified that 7.0+/-0.47 (n=4) and 1.4+/-0.58 (n=3) % of the injected dose per gram of liposomal 64Cu and free 64Cu remained in the blood pool, respectively. Our results suggest that this fast and easy 64Cu labeling of liposomes could be exploited in tracking liposomes in vivo for medical imaging and targeted delivery.     

Development of a new epidermal growth factor receptor positron emission tomography imaging agent based on the 3-cyanoquinoline core: Synthesis and biological evaluation

The epidermal growth factor receptor (EGFR/c-ErbB1/HER1) is overexpressed in many cancers including breast, ovarian, endometrial, and non-small cell lung cancer. An EGFR specific imaging agent could facilitate clinical evaluation of primary tumors and/or metastases. To achieve this goal we designed and synthesized a small array of fluorine containing compounds based on a 3-cyanoquinoline core. A lead compound, 16, incorporating 2′-fluoroethyl-1,2,3-triazole was selected for evaluation as a radioligand based on its high affinity for EGFR kinase (IC₅₀ = 1.81 ± 0.18 nM), good cellular potency (IC₅₀ = 21.97 ± 9.06 nM), low lipophilicity and good metabolic stability. ‘Click’ labeling afforded [¹⁸F]16 in 37.0 ± 3.6% decay corrected radiochemical yield based on azide [¹⁸F]14 and 7% end of synthesis (EOS) yield from aqueous fluoride. Compound [¹⁸F]16 was obtained with >99% radiochemical purity in a total synthesis time of 3 h. The compound showed good stability in vivo and a fourfold higher uptake in high EGFR expressing A431 tumor xenografts compared to low EGFR expressing HCT116 tumor xenografts. Furthermore, the radiotracer could be visualized in A431 tumor bearing mice by small animal PET imaging. Compound [¹⁸F]16 therefore constitutes a promising radiotracer for further evaluation for imaging of EGFR status.     

68Ga labeled Erlotinib: A novel PET probe for imaging EGFR over-expressing tumors

Molecular imaging using radiolabeled Tyrosine Kinase Inhibitors (TKI) is a promising strategy for detection and staging of EGFR-positive cancers. A novel analogue of one such TKI, Erlotinib has been developed for PET imaging by derivatizing the parent Erlotinib molecule for conjugation with the bifunctional chelator p-SCN-Bn-NOTA towards radiolabeling with ⁶⁸Ga. NOTA-Erlotinib conjugate was synthesized and characterized by NMR and ESI-MS techniques. The conjugate was radiolabeled with ⁶⁸Ga in 95 ± 2% yield, as evidenced by HPLC characterization. The log P value of ⁶⁸Ga-NOTA-Erlotinib was – (0.6 ± 0.1). The ⁶⁸Ga-NOTA-Erlotinib conjugate was characterized using its ^natGa-NOTA-Erlotinib surrogate. Cell viability studies showed that the NOTA-Erlotinib conjugate retained the biological efficacy of the parent Erlotinib molecule. Further, ⁶⁸Ga-NOTA-Erlotinib exhibited an uptake of 9.8 ± 0.4% in A431 cells which was inhibited by 55.1 ± 0.2% on addition of cold Erlotinib (10 µg) confirming the specificity of the radioconjugate for EGFR expressing cells. In the biodistribution studies carried out in tumor bearing SCID mice, ⁶⁸Ga-NOTA-Erlotinib conjugate showed moderate tumor accumulation (1.5 ± 0.1% ID/g at 30 min p.i.; 0.7 ± 0.2% ID/g at 1 h p.i.). Hepatobiliary clearance of the radioconjugate was observed. The ⁶⁸Ga-NOTA-Erlotinib conjugate was found to have high in vivo stability as determined by the metabolite analysis study using urine sample of the Swiss mice injected with the preparation. The overall properties of ⁶⁸Ga-NOTA-Erlotinib are promising and merit further exploration. To the best of our knowledge, this is the first report on the design of a ⁶⁸Ga labeled Erlotinib for PET imaging of EGFR and opens avenues for the successful development of ⁶⁸Ga labeled TKI for imaging of EGFR over-expressing tumors.     

Quantitative micro positron emission tomography (PET) imaging for the in vivo determination of pancreatic islet graft survival

Islet transplantation is an attractive approach for treating type-1 diabetes, but there is a massive loss of transplanted islets. It is currently only possible to estimate islet mass indirectly, through measurement of circulating C-peptide and insulin levels. This type of estimation, however, is not sufficiently sensitive or reproducible for follow-up of individuals who have undergone islet transplantation. Here we show that islet graft survival could be assessed for 1 month in diabetic NOD mice using 9-(4-[(18)F]-fluoro-3-hydroxymethylbutyl)guanine ([(18)F]FHBG)-positron emission tomography (PET) technology, the PET signal reflecting insulin secretory capacity of transplanted islets. Expression of the gene encoding viral interleukin-10 (vIL-10), was measurable in real time with PET scanning. Additionally, we addressed the clinical potential of this approach by visualizing transplanted islets in the liver, the preferred clinical transplantation site. We conclude that quantitative in vivo PET imaging is a valid method for facilitating the development of protocols for prolonging islet survival, with the potential for tracking human transplants.     

Synthesis of fluorinated analogues of sphingosine-1-phosphate antagonists as potential radiotracers for molecular imaging using positron emission tomography

Sphingosine-1-phosphate (S1P) receptors play major roles in cardiovascular, immunological and neurological diseases. The recent approval of the sphingolipid drug Fingolimod (Gilenya®), a sphingosine-1-phosphate agonist for relapsing multiple sclerosis, in 2010 exemplifies the potential for targeting sphingolipids for the treatment of human disorders. Moreover, non-invasive in vivo imaging of S1P receptors that are not available till now would contribute to the understanding of their role in specific pathologies and is therefore of preclinical interest. Based on fluorinated analogues of the S1P₁ receptor antagonist W146 showing practically equal in vitro potency as the lead structure, the first S1P receptor antagonist [¹⁸F]-radiotracer has been synthesized and tested for in vivo imaging of the S1P₁ receptor using positron emission tomography (PET). Though the tracer is serum stable, initial in vivo images show fast metabolism and subsequent accumulation of free [¹⁸F]fluoride in the bones.     

Noninvasive positron emission tomography imaging of cell death using a novel small-molecule probe, 18F labeled bis(zinc(II)-dipicolylamine) complex

The synthetic bis(zinc(II)-dipicolylamine) (DPAZn2) coordination complexes are known to have a high specific and selective affinity to target the exposed phosphatidylserine (PS) on the surface of dead and dying cells. An ¹⁸F-labeled DPAZn2 complex (4-¹⁸F-Fluoro-benzoyl-bis(zinc(II)-dipicolylamine), ¹⁸F-FB-DPAZn2) as positron emission tomography (PET) tracer was developed and evaluated for in vivo imaging of tumor treated with a chemical agent. The in vitro cell stain studies revealed that fluorescent DPAZn2 complexes (Dansyl-DPAZn2) stained the same cells (apoptotic and necrotic cells) as fluorescein isothiocyanate (FITC) labeled Annexin V (FITC-Annexin V). The radiosynthesis of ¹⁸F-FB-DPAZn2 was achieved through the amidation the precursor bis(2,2′-dipicolylamine) derivative (DPA2) with the prosthetic group N-succinimidyl-4-[¹⁸F]-fluorobenzoate (¹⁸F-SFB) and chelation with zinc nitrate. In the biodistribution study, the fast clearance of ¹⁸F-FB-DPAZn2 from blood and kidney was observed and high uptake in liver and intestine within 90 min postinjection was also found. For the PET imaging, significantly higher tumor uptake of ¹⁸F-FB-DPAZn2 was observed in the adriamycin (ADM)-treated Hepa1-6 hepatocellular carcinoma-bearing mice than that in the untreated tumor-model mice, while a slightly decreased tumor uptake of ¹⁸F-FDG was found in the ADM-treated tumor-bearing mice. The results indicate that ¹⁸F-FB-DPAZn2 has the similar capability of apoptosis detection as FITC-Annexin V and seems to be a potential PET tracer for noninvasive evaluation and monitoring of anti-tumor chemotherapy. The high uptake of ¹⁸F-FB-DPAZn2 in the abdomen needs to optimize the structure for improving its pharmacokinetics characteristics in the future work.     

Radiosynthesis of carbon-11-labeled camptothecin derivatives as potential positron emission tomography tracers for imaging of topoisomerase I in cancers

Four carbon-11-labeled camptothecin derivatives, 9-[11C]methoxy-20(S)-camptothecin ([11C]5), 10-[11C]methoxy-20(S)-camptothecin ([11C]7), 9-nitro-10-[11C]methoxy-20(S)-camptothecin ([11C]9), and 9-[([11C]trimethylamino)methyl]-10-hydroxy-20(S)-camptothecin ([11C]11), have been synthesized as potential positron emission tomography tracers for imaging of topoisomerase I in cancers.