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Purpose: The folate receptor (FR) is a promising target for nuclear imaging due to its overexpression in many different cancer types. A drawback of using folate radioconjugates is the high accumulation of radioactivity in the kidneys. Therefore, the aim of this study was to develop a 18 F-labeled folate conjugate with an albumin-binding entity to enhance the blood circulation time and hence improve the tumor-to-kidney ratio. Procedures: The novel 18 F-folate was prepared by conjugation of a 18 F-labeled glucose azide to an alkyne-functionalized folate precursor containing an albumin-binding entity via Cu(I)-catalyzed 1,3-dipolar cycloaddition. The radioconjugate was tested in vitro on FR-positive KB tumor cells and by biodistribution and positron emission tomography (PET) imaging studies using KB tumor-bearing mice. Results: The radiosynthesis of the albumin-binding [ 18 F]fluorodeoxyglucose–folate ([ 18 F]3) resulted in a radiochemical yield of 1–2 % decay corrected (d.c.) and a radiochemical purity of ≥95 %. The specific activity of [ 18 F]3 ranged from 20 to 50 GBq/μmol. In vitro experiments revealed FR-specific binding of [ 18 F]3 to KB tumor cells. In vivo we found an increasing uptake of [ 18 F]3 into tumor xenografts over time reaching a value of ∼ 15 % injected dose (ID)/g at 4 h post-injection (p.i.). Uptake in the kidneys (∼ 13 % ID/g; 1 h p.i.) was approximately fourfold reduced compared to previously published 18 F-labeled folic acid derivatives. An excellent visualization of tumor xenografts with an unprecedentedly high tumor-to-kidney ratio (∼ 1) was obtained by PET imaging. Conclusions: [ 18 F]3 showed a favorable accumulation in tumor xenografts compared to the same folate conjugate without albumin-binding properties. Moreover, the increased tumor-to-kidney ratios improved the PET imaging quality significantly, in spite of a somewhat higher background radioactivity which was a consequence of the slower blood clearance of [ 18 F]3. [ABSTRACT FROM AUTHOR]

The folate receptor (FR) is expressed in many tumor types, among those ovarian and lung cancer. Due to the high FR affinity of folic acid, it has been used for targeting of FR-positive tumors, allowing specific delivery of attached probes to the malignant tissue. Therefore, nuclear imaging of FR-positive cancer is of clinical interest for selecting patients who could benefit from innovative therapy concepts based on FR-targeting. Positron emission computed tomography (PET) has become an established technique in clinical routine because it provides an increased spatial resolution and higher sensitivity compared to single photon emission computed tomography (SPECT). Therefore, it is of critical importance to develop folate radiotracers suitable for PET imaging. This review article updates on the design, preparation and pre-clinical investigation of folate derivatives for radiolabeling with radioisotopes for PET. Among those the most relevant radionuclides so far are fluorine-18 (t½: 110 min, Eavβ+: 250 keV) and gallium-68 (t½: 68 min, Eav β+: 830 keV). Recent results obtained with new PET isotopes such as terbium-152 (t½: 17.5 h, Eβ+: 470 keV) or scandium-44 (t½: 3.97 h, Eav β+: 632 keV) are also presented and discussed. Current endeavors for clinical implementation of PET agents open new perspectives for identification of FR-positive malignancies in patients. [ABSTRACT FROM AUTHOR]

Radiolabeled folate derivatives have the potential to target folate receptor-positive tumor cells for noninvasive diagnosis via positron emission tomography (PET) and single photon emission computed tomography (SPECT). We report the regiospecific synthesis of N2-(N,N-dimethylaminomethylene)-2¢-nitrofolic acid di-tert-butyl ester (13) and N2-(N,N-dimethylaminomethylene)-N10- formyl-2¢-nitrofolic acid dimethyl ester (25), which are precursors for the radiolabeling of folic acid with the PET isotope 18F. A modular synthetic strategy was applied: Fmoc- and Boc-protected 4-amino- 2-nitrobenzoic acid were linked via amide bonds to di-tert-butyl L-glutamate and dimethyl L-glutamate, respectively, to form building blocks 10 and 19. After Fmoc and Boc removal, both compounds were coupled to 6-(bromomethyl)pterin hydrobromide to give crude 2¢-nitrofolic acid di-tert-butyl ester and 2¢-nitrofolic acid dimethyl ester. After formylation of 2¢-nitrofolic acid dimethyl ester at N10 and the introduction of an N,N-dimethylaminomethylene group at N2, precursor 25 was obtained in an overall yield of 3%. The analogous 2¢-fluoroderivative 28 was obtained in 7% overall yield from 4-amino-2-fluorobenzoic acid. Precursor 13 was obtained from 2¢-nitrofolic acid di-tert-butyl ester in 6% yield after N2-protection. The synthesis of the reference materials 2¢-nitro- and 2¢-fluorofolic acid was achieved by the reaction of N-(4-amino-2- nitrobenzoyl)- and N-(4-amino-2-fluorobenzoyl)-L-glutamic acid with 6-(bromomethyl)pterin hydrobromide, giving 7% and 14% overall yield, respectively. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Use of folic acid radioconjugates for folate receptor (FR) targeting is a promising strategy for imaging purposes as well as for potential therapy of cancer and inflammatory diseases due to the frequent FR overexpression found on cancer cells and activated macrophages. Herein, we report on preclinical results using a novel DOTA-Bz-EDA-folate conjugate radiolabeled with [67Ga]-gallium. Methods: DOTA-Bz-EDA-folate was prepared by conjugation of ethylenediamine-(γ)-folate with 2-(p-isothiocyanobenzyl)-DOTA. Radiolabeling was carried out with 67GaCl3 according to standard procedures. Biodistribution studies of the tracer were performed in mice bearing FR-positive KB tumor xenografts. The effects on radiofolate biodistribution with coadministered renal uptake-blocking amino acids, diuretic agents, antifolates as well as different routes of administration were likewise investigated. Supportive imaging studies were performed using a small-animal single photon emission computed tomography (SPECT)/CT scanner. Results: 67Ga-DOTA-Bz-EDA-folate showed a high and specific accumulation in tumors (6.30%±0.75% ID/g, 1 h pi and 6.08%±0.89% ID/g, 4 h pi). Nonspecific radioactivity uptake in nontargeted tissues was negligible, but significant accumulation was found in FR-positive kidneys, which resulted in unfavorably low tumor-to-kidney ratios (<0.1). Coadministered amino acids or diuretics did not effectively reduce renal accumulation; in contrast, predosed pemetrexed did significantly reduce kidney uptake (<29% of control values). The SPECT/CT studies confirmed the excellent tumor-to-background contrast of 67Ga-radiofolate and the favorable reduction in kidney uptake (with improved imaging quality) resulting from pemetrexed administration. Conclusion: Conventional methods to reduce kidney uptake of radiofolates fail. However, the novel 67Ga-radiolabeled DOTA-Bz-EDA-folate can effectively be used to image FR-positive cancer and potentially inflammatory diseases. Due to its rapid blood clearance properties, this tracer is also a promising candidate for positron emission tomography imaging if radiolabeled with the short-lived [68Ga]-gallium radionuclide. [Copyright &y& Elsevier]

Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two 55Co-labeled albumin-binding folate derivatives-[55Co]Co-cm10 and [55Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both 55Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [64Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors. [ABSTRACT FROM AUTHOR]