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Background and Aim: Guidelines on dyslipidemia and lipid-lowering therapy (LLT) over the years recommend lower low-density lipoprotein cholesterol (LDL-C) goals by more intense therapy. Nevertheless, LDL‑C has increased in the general population. Real-world trends of LLT medication as well as of LDL‑C levels in cardiovascular high-risk patients are unclear., Methods: From 2158 patients who were referred for elective coronary angiography, lipid medication was analyzed at admission in three cardiovascular observational studies (OS) over the last 25 years: OS1: 1999-2000, OS2: 2005-2008 and OS3: 2022-2023. The three studies were performed at the same cardiology unit of a tertiary care hospital in Austria., Results: The proportion of patients without LLT significantly decreased from OS1 through OS2 to OS3 (49.4%, 45.6%, and 18.5%, respectively, p trend  < 0.001). Moreover, the percentage of patients under high-intensity statin treatment significantly increased from 0% to 5.1%, and 56.5% (p trend  < 0.001). Significantly more patients became treated by more than one compound (OS1: 1.8%, OS2: 1.6%, OS3: 31.2%; p trend  < 0.001). In the latest OS3, a trend to fixed-dose combination of statins with ezetimibe was observed. Mean LDL‑C levels decreased from 129 mg/dL over 127 mg/dL to 83 mg/dL, respectively (p trend  < 0.001). Of the patients on high-intensity therapy 34% met the recent ESC/EAS goals (LDL-C < 55 mg/dL), but only 3% on non-intense therapy., Conclusion: We conclude that during the observational period of a quarter of a century, treatment intensity increased and LDL‑C levels improved considerably. Guidelines apparently matter in this high-risk population and are considered by primary care physicians., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

The folate receptor (FR) is an interesting target for radiotheranostics due to its overexpression in several tumor types. The progress in developing novel folate radioconjugates is, however, slow due to the synthetic challenges that folate chemistry presents. The goal of this study was, thus, to establish versatile solid-phase synthetic strategies for a convenient preparation of novel folate conjugates. Two approaches were established based on an orthogonal fluorenylmethyloxycarbonyl (Fmoc)-protection strategy to enable a modular buildup of an albumin-binding DOTA conjugate (known as OxFol-1) using folic acid (oxidized folate version) as a targeting agent. The main difference between the two approaches was the sequence of conjugating the single structural units. The approach that introduced the folate entity as the last unit appeared particularly useful for the preparation of conjugates based on 6 R - or 6 S -5-methyltetrahydrofolic acid (5-MTHF; a reduced folate version) as targeting entity. Three types of folate conjugates were synthesized either with a p -iodophenyl-based albumin binder (OxFol-1, 6 R -RedFol-1, and 6 S -RedFol-1) or without an albumin-binding entity (OxFol-14, 6 R -RedFol-14, and 6 S -RedFol-14). All six conjugates were obtained with high chemical purity (>98%) after 9-13 synthesis steps and a single final HPLC purification. Radiolabeling with lutetium-177 was feasible at high molar activity, and the resulting radioconjugates were stable over at least 24 h. Biodistribution and SPECT/CT imaging studies confirmed the favorable effect of an albumin-binding entity to increase the tumor uptake and reduce kidney retention of folate radioconjugates. The increased tumor-to-kidney ratios obtained with [ 177 Lu]Lu-6 R -RedFol-1 and [ 177 Lu]Lu-6 S -RedFol-1 as compared to [ 177 Lu]Lu-OxFol-1 indicated that 5-MTHF is the preferred FR-targeting agent for albumin-binding radioconjugates. This was, however, not the case for folate radioconjugates without an albumin binder. Thanks to the established synthesis strategy, the preparation of further folate radioconjugates will be facilitated, potentially enabling the optimization of the tissue distribution characteristics even more.

Purpose: The folate receptor (FR) is frequently overexpressed in a variety of tumor types and, hence, an interesting target for radionuclide therapy. The aim of this study was to evaluate a new class of albumin-binding radioconjugates comprising 5-methyltetrahydrofolate (5-MTHF) as a targeting agent and to compare their properties with those of the previously established folic acid-based [ 177 Lu]Lu-OxFol-1., Methods: [ 177 Lu]Lu-6R-RedFol-1 and [ 177 Lu]Lu-6S-RedFol-1 were investigated in vitro using FR-positive KB tumor cells. Biodistribution studies were performed in KB tumor-bearing mice, and the areas under the curve (AUC 0 → 120h ) were determined for the uptake in tumors and kidneys. [ 177 Lu]Lu-6R-RedFol-1 was compared with [ 177 Lu]Lu-OxFol-1 in a therapy study over 8 weeks using KB tumor-bearing mice., Results: Both radioconjugates demonstrated similar in vitro properties as [ 177 Lu]Lu-OxFol-1; however, the tumor uptake of [ 177 Lu]Lu-6R-RedFol-1 and [ 177 Lu]Lu-6S-RedFol-1 was significantly increased in comparison with [ 177 Lu]Lu-OxFol-1. In the case of [ 177 Lu]Lu-6S-RedFol-1, also the kidney uptake was increased; however, renal retention of [ 177 Lu]Lu-6R-RedFol-1 was similar to that of [ 177 Lu]Lu-OxFol-1. This led to an almost 4-fold increased tumor-to-kidney AUC 0 → 120h ratio of [ 177 Lu]Lu-6R-RedFol-1 as compared with [ 177 Lu]Lu-6S-RedFol-1 and [ 177 Lu]Lu-OxFol-1. At equal activity, the therapeutic effect of [ 177 Lu]Lu-6R-RedFol-1 was better than that of [ 177 Lu]Lu-OxFol-1, reflected by a slower tumor growth and, consequently, an increased median survival time (49 days vs. 34 days)., Conclusion: This study demonstrated the promising potential of 5-MTHF-based radioconjugates for FR-targeting. Application of [ 177 Lu]Lu-6R-RedFol-1 resulted in unprecedentedly high tumor-to-kidney ratios and, as a consequence, a superior therapeutic effect as compared with [ 177 Lu]Lu-OxFol-1. These findings, together with the absence of early side effects, make [ 177 Lu]Lu-6R-RedFol-1 attractive in view of a future clinical translation.