Synthesis and preclinical evaluation of BOLD-100 radiolabeled with ruthenium-97 and ruthenium-103.

BOLD-100 (formerly IT-139, KP1339), a well-established chemotherapeutic agent, is currently being investigated in clinical trials for the treatment of gastric, pancreatic, colorectal, and bile duct cancer. Despite numerous studies, the exact mode of action is still the subject of discussions. Radiolabeled BOLD-100 could be a powerful tool to clarify pharmacokinetic pathways of the compound and to predict therapy responses in patients using nuclear molecular imaging prior to the therapy. In this study, the radiosyntheses of carrier-added (c.a.) [97/103Ru]BOLD-100 were performed with the two ruthenium isotopes ruthenium-103 (103Ru; ß-, γ) and ruthenium-97 (97Ru; EC, γ), of which in particular the latter isotope is suitable for imaging by single-photon emission computed tomography (SPECT). To identify the best tumor-to-background ratio for diagnostic imaging, biodistribution studies were performed with two different injected doses of c.a. [103Ru]BOLD-100 (3 and 30 mg kg-1) in Balb/c mice bearing CT26 allografts over a time period of 72 h. Additionally, ex vivo autoradiography of the tumors (24 h p.i.) was conducted. Our results indicate that the higher injected dose (30 mg kg-1) leads to more unspecific accumulation of the compound in non-targeted tissue, which is likely due to an overload of the albumin transport system. It was also shown that lower amounts of injected c.a. [103Ru]BOLD-100 resulted in a relatively higher tumor uptake and, therefore, a better tumor-to-background ratio, which are encouraging results for future imaging studies using c.a. [97Ru]BOLD-100.

Position paper on requirements for toxicological studies in the specific case of radiopharmaceuticals.

This is a position paper of the Radiopharmacy Committee of the EANM (European Association of Nuclear Medicine) addressing toxicology studies for application of new diagnostic and therapeutic radiopharmaceuticals (RP) that are not approved (i.e., not having a marketing authorization or a monograph in the European Pharmacopoeia), excluding endogenous and ubiquitous substances in humans. This paper discusses the requirements for clinical trials with radiopharmaceuticals for clinical research applications, not necessarily intended to aim at a marketing authorization. If marketing authorization is intended, scientific advice of the competent authorities is mandatory and cannot be replaced by this position paper. The position paper reflects the view of the Radiopharmacy Committee of the EANM and can be used as a basis for discussions with the responsible authorities.

Guidance on validation and qualification of processes and operations involving radiopharmaceuticals.

BACKGROUND: Validation and qualification activities are nowadays an integral part of the day by day routine work in a radiopharmacy. This document is meant as an Appendix of Part B of the EANM "Guidelines on Good Radiopharmacy Practice (GRPP)" issued by the Radiopharmacy Committee of the EANM, covering the qualification and validation aspects related to the small-scale "in house" preparation of radiopharmaceuticals. The aim is to provide more detailed and practice-oriented guidance to those who are involved in the small-scale preparation of radiopharmaceuticals which are not intended for commercial purposes or distribution. RESULTS: The present guideline covers the validation and qualification activities following the well-known "validation chain", that begins with editing the general Validation Master Plan document, includes all the required documentation (e.g. User Requirement Specification, Qualification protocols, etc.), and leads to the qualification of the equipment used in the preparation and quality control of radiopharmaceuticals, until the final step of Process Validation. CONCLUSIONS: A specific guidance to the qualification and validation activities specifically addressed to small-scale hospital/academia radiopharmacies is here provided. Additional information, including practical examples, are also available.

Electrocyclic ring closure of the enols of vinyl quinones. A 2H-chromene synthesis.

Thermolysis of enolizable vinyl quinones in polar, aprotic media provides 2H-chromenes. Experimental evidence supports a two-step mechanism in which enolization is followed by a thermal 6pi-electrocyclic reaction of an intermediate quinone methide. Application of this method led to the total synthesis of the reputed structure of an Ageratum juvenile hormone. When enolizable vinyl quinones are the products of Stille coupling, the chromene annulation product is obtained directly. [reaction: see text]