**2.4 Uncategorized tracer**

254 12 Chapters on Nuclear Medicine

and single photon imaging including SPECT, and to PET. However, most of the radiolabeled annexin V used in clinical trials are 99mTc labeled annexin V, because 99mTc is characterized by the most suitable radionuclide properties for SPECT imaging in human

99mTc-BTAP-annexin V using a diamide dimercaptide N2S2 chelate for labeling (99mTc- N2S2 annexin V) was introduced in early 1990s and examined to detect left atrial thrombi in vivo in swine (Stratton et al., 1995). Biodistribution and dosimetry study of 99mTc-BTAP-annexin V in patients revealed that the radioactivity predominates in kidney, liver and urine bladder and fast and extensive bowel excretion of the tracer precludes the assessment of abdominal region (Kemerink, et al., 2001a). N2S2 labeling method is cumbersome but radiochemical yield is low

Accordingly, an improved labeling method using the bifunctional agent hydrazinonicotinamide (HYNIC) was introduced (Blankenberg, et al., 1998). 99mTc-labeling of reconstituted HYNIC-annexin V can be performed by simply reacting the conjugate with 99mTc-pertechnetate in the presence of stannous tricine for 5-10min in room temperature and it provides 99mTc-HYNIC-annexin V in high radiochemical yield (usually 92-95%) without requiring any additional purification step. Phase I clinical trial with 99mTc-HYNIC-annexin V also demonstrated strongest uptake in kidney, liver and urine bladder. However, in contrast to 99mTc-BTAP-annexin V no bowel excretion was observed in 99mTc-HYNIC-annexin V, having a favorable biodistribution for imaging of the abdominal as well as thoracic area. As an alternative methods for radiolabeling annexin V, self chelating annexin V mutants had been introduced (Tait, et al., 2000, 2005). Annexin V mutants with endogeneous site for 99mTc chelation such as V-117 and V-128 have major advantages over the HYNIC chelatior in terms with lower renal retention. Many other kind of 99mTc-labeled annexin V have been introduced, however, only 99mTc-i-annexin V (Kemerink, et al., 2001b) was tested in clinical

As a PET tracer, several approaches to label annexin V with 18F have been developed (Grierson, et al. 2004; Murakami et al., 2004).18F-annexin V has lower uptake in the liver,

C2A domain of synaptotagmin I also binds PS with nanomolar affinity in a calciumdependent manner. The C2A is labeled in the form of C2A-GST (GST: glutathione Stransferase) fusion protein. The fusion protein can be stably labeled with 99mTc at a reasonably high radiochemical yield and purity through thiolation using 2-iminothiolane (Zhao, et al., 2006). 99mTc-C2A-GST accumulates well in the area at risk in a rat model of acute myocardial infarction in both in-vivo imaging and autoradiography. Recently, 18F-C2A-GST was synthesized and significant uptake in the VX2 rabbit lung cancer with paclitaxel induced apoptosis was observed in small animal PET/CT (Wang, et al., 2011). Radiochemical purity of 18F-C2A-GST was more than 95% and stable for 4 h after formulation. Biodistribution in mice was favorable with major excretion from the kidneys

Caspase activation is the central role in the execution of cell death, therefore, caspases are the attractive targets for apoptosis imaging. Non-peptide based isatin sulfonamide analogs were synthesized with nanomolar potency for inhibiting caspase-3 and caspase-7 and one of

and had a high degree of non specific tracer excretion into bowel via excretion to bile.

trial in addition to 99mTc-BTAP-annexin V and 99mTc-HYNIC-annexin V.

spleen, and kidneys than 99mTc-HYNIC-annexin V.

and rapid clearance from blood and nonspecific organs.

**2.3 Radiolabeled caspase targeted tracer** 

**2.2 Radiolabeled C2A** 

and is inexpensive and easily available.

Recently a novel family of low molecular mass amphipatic apoptosis markers (ApoSense) was developed targeting the cell membrane of apoptotic cells. 18F-labeled 5-fluoropentyl-2 methyl-malonic acid (18F-ML-10) belongs to this family of low-molecular-weight compounds used for the imaging of cell death in vivo. This compound responds to alterations in plasma membrane potential and phospholipid scrambling, which are hallmarks of apoptotic cells. To which cell membrane targets this probe binds is unknown. After systemic administration, the compound can detect apoptotic cells from the early stages of the death process, cross the intact plasma membrane, and accumulate in the cytoplasm. In animal model of cerebral infarction, selective uptake was observed in the region of ischemia at 24 hr after the middle cerebral artery occlusion (Reshef et al., 2008).
