A Closer Look at the Bromine–Lithium Exchange with <i>tert</i>-Butyllithium in an Aryl Sulfonamide Synthesis

A practical protocol for the one-pot synthesis of various aryl sulfonamides, notably of pyridine-core-substituted 7-azaindolyl sulfonamides, is described. A key step is the well-known bromine–lithium exchange reaction of an aryl bromide with <i>tert</i>-butyllithium (<i>t</i>-BuLi). Differing from the common practice to use 2 or more equiv of organolithium, the exact amount of <i>t</i>-BuLi needed for a sufficient exchange reaction is determined for each aryl bromide in a GC–MS-assisted experiment

Receiver Operator Curve for diagnostics of acute rat renal allograft rejection by FDG-PET.

<p>The curve is the regression line that summarizes the overall diagnostic accuracy. A perfect prediction would yield AUC = 1 (area under the curve), whereas AUC = 0.5 would suggest predictive accuracy equal to that of chance alone. Thus, the area measures discrimination that is, the ability of the test to correctly classify those with and without the disease. AUC was 0.973.</p

Correlation between the FDG uptake of graft kidneys expressed in percentage of the injected dose (%ID) and the ratio of FDG uptake of graft kidney to control kidney.

<p>A significant correlation of the ratio and the percent injected dose was found (r² = 0.69).</p

The four outcomes in a contingency table.

<p>ID: injected dose; true positive rate: 0.92 (23 out of 25); false positive rate: 0.01 (1 out of 81).</p

Detection of acute rejection by measurement of the %ID of FDG within renal allografts.

<p>Kidneys undergoing acute rejection showed a clearly increased FDG-uptake starting from the first postoperative day (POD 1) (0.54±0.06%, n = 5 vs. 0.22±0.02%, n = 13, in controls). The %ID of allogeneic transplants rose further until POD 4 (0.58±0.12%, n = 5, POD 2, and 0.81±0.06%, n = 5, POD 4), while that of native kidneys remained the same (0.2±0.03%, n = 5, day 4). Towards POD 7 the %ID of allografts remained stable (0.77±0.1%, n = 5). The %ID of syngeneic transplanted controls was 0.37±0.04% (n = 5, POD 4). This was not significantly different to controls but to aTX (p<0.05). The FDG uptake of kidneys with acute tubular necrosis (ATN: POD1: 0.25±0.02%, POD2: 0.21±0.04%, POD4: 0.31±0.02%, n = 3) or acute cyclosporine A toxicity (CSA: 0.24±0.03%, POD2: 0.19±0.01%, POD4: 0.16±0.01%, n = 3) was not significantly different to that of control kidneys.</p

Relation of the ¹⁸F-fluoride clearance (ml/min) to the FDG uptake (%ID).

<p>No correlation of these two parameters was found (R² = 0.005, n = 22).</p

Representative PET-images of dynamic whole body acquisitions of a series of an allogeneically transplanted rat (aTX) (POD 1 (A), 2 (B), 4 (C), and 7 (D), after tail vein injection of 30 MBq FDG (maximum a posterior (MAP) projection, 180 min p.i.).

<p>While the parenchyma (yellow circle) of renal allograft accumulates FDG with a maximum on POD 4, the native kidney (green circle) does not show any accumulation at any time. Please note that the renal pelvis can contain eliminated FDG. Therefore, it was excluded from the measurements.</p

Signs of acute rejection, namely glomerulitis, tubulitis, endothelialitis, and graft infiltration, were found in the allograft group (aTX) starting from POD 1 (A).

<p>Nevertheless, graft integrity was confirmed on POD 1, 2, and 4. In contrast, histology of POD 7 showed the appearance of necrosis and hemorrhage within the allograft. No histological signs of rejection were found in native controls (leukocytes: 12±1/FOV, n = 18) or syngeneic transplants (sTX) (leukocytes: 26±4/FOV, n = 6). Leukocyte infiltration in kidneys with acute tubular necrosis (ATN, POD4, leukocytes: 17±3/FOV, n = 3) was moderate and emphasized in the outer medulla, while kidneys with acute cyclosporine toxicity (CSA) presented with only 7±1/FOV leukocytes (POD 4, n = 6). In allografts significant infiltration was found since POD 1 (B) (leukocytes: 77±2/FOV, all groups p<0.05 vs. sTX and CTR, n = 6). It aggravated on POD 2 (leukocytes: 98±12/FOV), peaked on POD 4 (leukocytes: 142±4/FOV), and was slightly lower on POD 7 (leukocytes: 115±2/FOV).</p

Representative micro-autoradiography of an allogeneically (aTX), a syngeneically transplanted kidney (sTX), a kidney with acute tubular necrosis (ATN), two kidneys with acute cyclosporine A toxicity (CSA), and control kidneys 180 min p.i. of 30 MBq FDG, 4 days after surgery or treatment, respectively.

<p>Control kidneys (A–C, right kidneys) showed low mean FDG-uptake/mm² in the mid-coronary slice. FDG-uptake of the allograft (A, aTX: 1.22 cpm/mm²/MBq) increased by nearly 7 times when compared to control (A, CTR: 0.18 cpm/mm²), while the FDG uptake in the syngeneic transplant (B, sTX: 0.26 cpm/mm²) was 1.52 times that of control (B, CTR: 0.17 cpm/mm²). FDG-uptake of the kidney with ATN (C, ATN: 0.19 cpm/mm²) was 1.58 times that of control (C, CTR: 0.12 cpm/mm²), while the FDG-uptake in the kidneys with acute CSA toxicity (D, left: 0.13 cpm/mm², right: 0.14 cpm/mm²) was even lower. Notably, in ATN the FDG-uptake clearly emphasizes the outer medulla region.</p

A New Generation of Radiofluorinated Pyrimidine-2,4,6-triones as MMP-Targeted Radiotracers for Positron Emission Tomography

Radiolabeled C-5-disubstituted pyrimidine-2,4,6-triones have recently been suggested by our group as a class of potent matrix metalloproteinase (MMP) targeted radiotracers that can noninvasively visualize activated MMPs by means of positron emission tomography (PET). MMPs belong to the zinc- and calcium-dependent endopeptidases which are involved in the proteolytic degradation of components of the extracellular matrix (ECM) but also are capable of processing and releasing bioactive molecules such as growth factors, proteinase inhibitors, and cytokines. Locally increased levels of activated MMPs modulate and contribute to the progression of various diseases, such as cancer, atherosclerosis, stroke, arthritis, and others. Therefore, activated MMPs are suitable biological targets for the specific and noninvasive visualization of aforementioned pathologies in vivo. On the basis of our recent results, we here describe a series of new fluorinated pyrimidine-2,4,6-triones of the second generation with maintained MMP inhibition potencies (IC₅₀ = 4–605 nM), which are fine-tuned toward more hydrophilic versions, and show the improved biodistribution behavior of one selected radiofluorinated pyrimidine-2,4,6-trione by means of small-animal PET