C-11 Radiochemistry in Cancer Imaging Applications

Fan

Nuclear Medicine and Biology

2017

Introduction Aspects of radiopharmaceutical development are illustrated through preclinical studies of [125I]-(E)-1-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA- BF-PE-PIPZE), a radioligand for sigma-1 (σ1) receptors, coupled with examples from the recent literature. Findings are compared to those previously observed for [125I]-(E)-1-(2-(2,3-dimethoxy-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA-DM-PE-PIPZE). Methods Syntheses of E-IA-BF-PE-PIPZE and [125I]-E-IA-BF-PE-PIPZE were accomplished by standard methods. In vitro receptor binding studies and autoradiography were performed, and binding potential was predicted. Measurements of lipophilicity and protein binding were obtained. In vivo studies were conducted in mice to evaluate radioligand stability, as well as specific binding to σ1 sites in brain, brain regions and peripheral organs in the presence and absence of potential blockers. Results E-IA-BF-PE-PIPZE exhibited high affinity and selectivity for σ1 receptors (Ki = 0.43 ± 0.03 nM, σ2 / σ1 = 173). [125I]-E-IA-BF-PE-PIPZE was prepared in good yield and purity, with high specific activity. Radioligand binding provided dissociation (koff) and association (kon) rate constants, along with a measured Kd of 0.24 ± 0.01 nM and Bmax of 472 ± 13 fmol / mg protein. The radioligand proved suitable for quantitative autoradiography in vitro using brain sections. Moderate lipophilicity, Log D7.4 2.69 ± 0.28, was determined, and protein binding was 71 ± 0.3%. In vivo, high initial whole brain uptake, > 6% injected dose / g, cleared slowly over 24 h. Specific binding represented 75% to 93% of total binding from 15 min to 24 h. Findings were confirmed and extended by regional brain biodistribution. Radiometabolites were not observed in brain (1%). Conclusions Substitution of dihydrobenzofuranylethyl for dimethoxyphenethyl increased radioligand affinity for σ1 receptors by 16-fold. While high specific binding to σ1 receptors was observed for both radioligands in vivo, [125I]-E-IA-BF-PE-PIPZE displayed much slower clearance kinetics than [125I]-E-IA-DM-PE-PIPZE. Thus, minor structural modifications of σ1 receptor radioligands lead to major differences in binding properties in vitro and in vivo.

Section: Sigma Receptors and Ligand Designmentioning

confidence: 99%

Tactics for preclinical validation of receptor-binding radiotracers

Fan

Nuclear Medicine and Biology

2017

Labelled Comp Radiopharmac

“…Finally, the organic nitrile function thus introduced can be converted to a variety of chemical modifications, allowing the preparation of a wide array of carbon‐isotope labeled compounds . While 14 C‐labeled compounds are an essential tool to get market access for crop protection products, and 14 C‐labeled active pharmaceutical ingredients are still the main radioactive markers for several pharmaceutical studies including human metabolism studies, carbon‐11 labeled compounds are widely used radiotracers for drug development …”

Section: Introductionmentioning

confidence: 99%

New trends and applications in cyanation isotope chemistry

Derdau

2018

In this review, newly developed cyanation methods are evaluated in regards to their usefulness in synthetic isotope chemistry. In combination with already established protocols in C- or C-isotope chemistry, this manuscript should help isotope scientists to choose the best possible method for their scientific cyanation problem, but with the main focus on C-applications. Perhaps, most promising of the described novel cyanation reaction is the decarboxylation-cyanation-hydrolysis approach which makes a 1-step late-stage functionalization procedure possible.

Labelled Comp Radiopharmac

“…One major 11 C precursor used in the synthesis is [ 11 C]‐CO 2 (the other being [ 11 C]‐CH 4 ) . To date, the most frequently used method for the introduction of 11 C into organic molecules is the methylation . Methylations with this isotope are limited to the labeling of molecules at functional groups at peripheral atomic positions.…”

Section: Introductionmentioning

confidence: 99%

Recent developments in heterocycle labeling with carbon isotopes

Vecchio

Destro

Taran

2018

Heterocycles play an essential role in modern pharmaceutical and agrochemical developments, representing a very common structural unit in marketed drugs. Over the 46 new drugs approved in 2017 by the FDA, 25 contain in their structure a heterocyclic core. The development of novel and straightforward labeling strategies for the effective insertion of carbon isotopes into heterocylic scaffolds is an inspiring and vibrant field of research. The use of carbon-11, carbon-13, and carbon-14 isotopes is well established in life science and particularly in pharmaceutical and agrochemical industry. Their introduction into small organic molecules represents a crucial step for the radiochemists. Because the labeling should occur in metabolically stable positions and in the shortest synthetic route, their incorporation into the heterocycles represents a viable solution. This review summarizes recent contributions to this area of research through the analysis of different industrial and academic cases.