[DOTA]Somatostatin-14 analogs and their (111)In-radioligands: effects of decreasing ring-size on sst1-5 profile, stability and tumor targeting.

Multiple somatostatin receptor (sst)-subtype expression has been manifested in several human tumors. Hence, the availability of radiopeptides retaining the full pansomatostatin profile of the native hormone (SS14) is expected to increase the sensitivity and broaden the clinical indications of currently applied sst2-preferring cyclic octapeptide radioligands, like OctreoScan(®) ([(111)In-DTPA]octreotide). On the other hand, SS14 has been excluded from clinical use due to its rapid in vivo degradation. We herein present a small library of seven novel cyclic SS14-mimics carrying at their N-terminus the universal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) for stable binding of medically useful radiometals, like (111)In. By decreasing the number of amino acids composing the ring in their structure from 12 up to 6 AA, we induced important changes in key-biological parameters in vitro and in vivo. In particular, we observed unexpected changes and even total loss of sst1-5-affinity (6AA-ring), as well as weaker sst2-internalization efficacy as the ring size decreased. In contrast, in vivo stability increased with decreasing ring size, reaching its maximum in the 6AA-ring analogs. Interestingly, only the 12AA- and 9AA-ring members of this series showed sst2-specific uptake in AR4-2J tumors in mice revealing the prominent role of ring size on the biological response of tested SS14-derived radioligands.

Stereochemistry of Amino Acid Spacers Determines the Pharmacokinetics of (111)In-DOTA-Minigastrin Analogues for Targeting the CCK2/Gastrin Receptor.

The metabolic instability and high kidney retention of minigastrin (MG) analogues hamper their suitability for use in peptide-receptor radionuclide therapy of CCK2/gastrin receptor-expressing tumors. High kidney retention has been related to N-terminal glutamic acids and can be substantially reduced by coinjection of polyglutamic acids or gelofusine. The aim of the present study was to investigate the influence of the stereochemistry of the N-terminal amino acid spacer on the enzymatic stability and pharmacokinetics of (111)In-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-D) and (111)In-DOTA-(l-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-L). Using circular dichroism measurements, we demonstrate the important role of secondary structure on the pharmacokinetics of the two MG analogues. The higher in vitro serum stability together with the improved tumor-to-kidney ratio of the (d-Glu)6 congener indicates that this MG analogue might be a good candidate for further clinical study.

Ms. hebr. oct. 111 - Seliḥot u-piyuṭim

Vorbesitzer: Abraham Merzbacher

Ms. Barth. 111 - Frühscholastische Sammelhandschrift

Vorbesitzer: Rotger Overhach de Tremonia; Bartholomaeusstift Frankfurt am Main

Ms. lat. qu. 111 - Akten und Flugschriften, vor allem zum Franchigienstreit und zur französischen Kirchengeschichte

Die Foliierung weicht von den Angaben des Kataloges ab; die Foliierung geht nur bis Bl. 210; zusätzlich gibt es die Blätter 144a, 153a und 202a.

Zeenah ureenah : Vgl. Jahrbuch f. jüd. Volkskunde, 1924/25, S. 111

S. Bamberger

Ms. germ. qu. 111 - Historia Hierosolymitana deutsch

Vorbesitzer: Kloster Bronnbach; Kloster Neustadt a. M.; Fürstlich Löwenstein-Rosenbergische Hofbibliothek Klein-Heubach; Freiherrlich Carl von Rothschild'sche Bibliothek Frankfurt am Main

Ms. Praed. 111 - Philosophica

Vorbesitzer: Dominikanerkloster Frankfurt am Main

Na 50 Nachlass Arthur Schopenhauer - 'Schopenhauer-Archiv', 111 - Übersendung eines korrigierten Gedichts

u.a.: Durand;

Ms.Ff.F.Stoltze 3. 111 - Brief von Friedrich Haussmann an Franz Schreiber

Kondolation zum Tode Stoltzes, Ludwig Pfau

Fragm. germ. III 4 - Facetus 'Cum nihil utilius', lat.-dt. (V. 96 - 102, 105 - 111). Disticha Catonis, lat.-dt. (IV 32 - 43)

Trägerband: Inc. qu. 1272; Vorbesitzer: Dominikanerkloster Frankfurt am Main

Ms. lat. oct. 111 - Stundenbuch nach dem Gebrauch von Rom

Vorbesitzer: Friedrich Wilhelm Graf von Schlabrendorff

Ms. or. 111 - Hl. Georg, den Drachen tötend

Vorbesitzer: Eduard Rüppell